anti-GBM Glomerulonephritis Research Articles

MO939RECURRENCE AND OUTCOME OF ANTI-GLOMERULAR BASEMENT MEMBRANE GLOMERULONEPHRITIS AFTER KIDNEY TRANSPLANTATION: A BELGIAN MULTICENTER STUDY

Abstract Background and Aims Recurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited case reports and registry analysis. The aim of this study was to evaluate in a large cohort of patients with detailed data collection and long follow-up the risk of recurrence of anti-GBM disease and graft loss caused by recurrence, the risk factors associated with clinical recurrence and the long-term patient and graft survival. Method Multicenter retrospective study. Inclusion criteria: patients with anti-GBM glomerulonephritis transplanted with a kidney between 1977 and 2015. Exclusion criteria: systemic vasculitis (except ANCA), lupus erythematosus and cryoglobulinemia. Clinical recurrence was defined as reappearance of signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies. Results Fifty-three patients were included. Clinical recurrence in a first kidney transplant occurred in only one patient five years after transplantation -a prevalence rate of 1.9%- in the context of cessation of immunosuppressive drugs. The graft was lost due to recurrence. Histological recurrence with linear IgG staining on kidney biopsy in the absence of histologic signs of proliferative glomerulonephritis was observed in four patients, in the context of cellular rejection. Two patients lost their kidney graft from severe acute rejection; the others fully recovered. Patient survival was 100%, 94% and 89% at 5, 10 and 15 years, respectively. Overall, death-censored first graft survival rates were 88%, 83% and 79% at 5, 10 and 15 years, respectively. Conclusion Recurrence rate of anti-GBM glomerulonephritis after transplantation is very low, and associated with graft loss. The long-term patient and graft survival rates are excellent.

Recurrence and Outcome of Anti−Glomerular Basement Membrane Glomerulonephritis After Kidney Transplantation

IntroductionRecurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited reports. The aim of this study was to evaluate, in a large cohort of patients with long follow-up, the risk of recurrence of anti-GBM disease, the risk factors associated with clinical recurrence, and the long-term patient and graft survival.MethodsThis was a multicenter retrospective study. Inclusion criteria were patients with anti-GBM glomerulonephritis who underwent transplantation of a kidney between 1977 and 2015. Exclusion criteria were systemic vasculitis, lupus erythematosus, and cryoglobulinemia. Recurrence was defined as reappearance of clinical signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies.ResultsA total of 53 patients were included. Recurrence of anti-GBM glomerulonephritis in a first kidney transplant occurred in only 1 patient 5 years after transplantation (a prevalence rate of 1.9%) in the context of cessation of immunosuppressive drugs, and resulted in graft loss due to recurrence. Linear IgG staining on kidney biopsy in the absence of histological signs of proliferative glomerulonephritis was observed in 4 patients, in the context of cellular rejection. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. Death-censored first-graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years, respectively.ConclusionThe recurrence rate of anti-GBM glomerulonephritis after transplantation is very low but is associated with graft loss. The long-term patient and graft survival rates are excellent.

P208 A case of double positivity

Abstract Background/Aims In the absence of renal or lung involvement, the investigation of small vessel vasculitis does not routinely include checking of anti-glomerular basement membrane (GBM) antibodies. We present a patient with an MPO-ANCA positive vasculitic neuropathy who later developed anti-GBM positive glomerulonephritis. We review the literature on patients who are “double-positive” for ANCA and GBM antibodies and speculate on the utility of routinely screening all vasculitis patients for GBM antibodies in the absence of manifestations of Goodpasture’s syndrome. Methods We describe a 70 year old female who presented feeling generally unwell with reduced mobility due to discomfort in her feet. Examination was unremarkable, except for reduced temperature and joint position sense in the feet. CRP was elevated and she was found to have a weakly positive MPO titre of 32. She was treated as an MPO-ANCA positive vasculitis and neuropathy with steroids and Mycophenolate Mofetil, with a good clinical and biochemical response. Fifteen months into her treatment, routine monitoring revealed an acute kidney injury with a creatinine of 459 umol/l from a baseline of 88. Anti GBM titres were requested for the first time as part of the renal screen. MPO antibody titres were only 9, but GBM antibody titres were markedly elevated (>200). Renal biopsy showed focal necrotising glomerulonephritis, in keeping with anti-GBM disease. She was treated with steroids, cyclophosphamide and plasma exchange by the renal physicians. She remains dialysis dependant. Results In our patient, GBM antibodies were only requested once she developed relevant clinical manifestations of anti-GBM disease. This in contrast to nephrology practise, where ANCA and GBM antibodies are routinely requested simultaneously in the context of nephritis. It could be speculated that if the GBM antibody status had been detected sooner, we may have altered her management and possibly improved her disease course. Anti-GBM disease and ANCA-associated vasculitis are both rare conditions. However, co-existence of the two uncommon diseases in individual patients is well-described and more than chance occurrence. A study showed that 5% of ANCA-positive cases were also positive for anti-GBM antibodies, while one-third of anti-GBM positive samples had detectable ANCA. Multiple studies have shown that low level ANCA antibodies develop months to years before onset of anti-GBM disease, as seen in our patient as well.The dominant disease phenotype in double positive patients is anti-GBM disease rather than vasculitis. It is very rare for isolated anti-GBM disease to relapse. In contrast, half of double positive patients experience disease relapse and therefore, require long-term follow-up and maintenance immunosuppression. Conclusion Awareness of this double positive phenomenon is important. Rheumatologists do not routinely check anti-GBM in all vasculitis. This case highlights the importance of doing so, especially in atypical presentation of vasculitis or in relapse and refractory disease. Disclosure S. Khalid: None. J. Li: None. S. Young Min: None.

POS-499 CLINICAL AND PATHOLOGY SPECTRUM OF NON-AMYLOID MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE – ONE CENTER EXPERIENCE

In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term monoclonal gammopathy of renal significance (MGRS) to highlight causal relationship between gammopathy and monoclonal immunoglobulin (MIg)-mediated renal damage in cases, which do not meet criteria for B-cell malignancies. MGRS spectrum included various patterns with organized and non-organized paraprotein deposition: light chain proximal tubulopathy (LCPT), crystal-storing histiocytosis, MIg related amyloidosis, monoclonal fibrillary glomerulonephritis (GN), immunotactiod GN, type I cryoglobulinemic glomerulonephritis (cryo-GN), MIg deposition disease (MIDD), proliferative GN with MIg deposits (PGNMID), and C3-glomerulonephritis (C3-GN). According to the IKMG 2019 Consensus report, MGRS in addition to the above listed variants now merges type II cryo-GN, (cryo)-crystalglobulin GN, thrombotic microangiopathy associated with monoclonal gammopathy, monotypic membranous nephropathy (MN), monotypic anti-glomerular basement (anti-GBM) GN, smoldering myeloma (SM), smoldering Waldenström’s macroglobulinemia (SWM), and low-grade B-cell non-Hodgkin lymphoma (B-cell NHL) associated with renal lesions. Cast-nephropathy (CN) regarded as myeloma-defining event, and as such - does not belong to the MGRS, even though it is not exclusive to multiple myeloma. Same, intracapillary MIgM deposits, traditionally attributed to overt Waldenström’s macroglobulinemia, not included into MGRS list For this retrospective study, we evaluated 87 cases matching the updated MGRS criteria and followed in our unit in 2002-2020. The main data collected were clinical diagnosis, proteinuria, eGFR (CKD-EPI equation), need for dialysis at the time of kidney biopsy, and pathology pattern. Pathology evaluation of kidney tissue per protocol included light microscopy and immune staining; with the electron microscopy additionally performed 9% of cases. MGRS diagnosis based on evaluation of kidney pathology findings, serum and urine immunochemistry, and bone marrow biopsy. For this particular study, we evaluated non-amyloid variants of MGRS and non-amyloid patterns presenting in combination with MIg amyloidosis, and excluded from further analysis cases of “pure” MIg related amyloidosis. Study group included 29 patents - 9 males and 20 females of mean age 64 [53; 82] years; 8 patients were ultimately diagnosed with SM, 6 - with SWM, 2- with low-grade B-cell NHL, the rest 13 had no underlying hematological disease. At the time of kidney biopsy nephrotic syndrome presented in 16 (55%) of cases; 6 patients had CKD stage G2, 4 - stage G3a, 5 - stage G3b, 10 - stage G4, and 4 - stage 5, two of the latter required dialysis at the time of biopsy. Pathology patterns shown in the Table 1 Patterns with the organized MIg deposits presented mostly in SM cases, whereas non-organized deposits, mainly MIDD, dominated in patients without underlying hematological condition and in cases of SWM. The combination of organized and non-organized MIg deposits found rarely - both in SM and in cases without underlying hematological condition. Amyloidosis was combined with other patterns in 4 cases. Single cases of C3-GN alone and in combination with LCPT revealed only in SM and SWM. Importantly, we found 3 cases of SM with CN and 2 cases of SWM with intracapillary deposits MIgM, which complement the MGRS spectrum

Nephrotic syndrome due to minimal-change disease superimposed on anti-glomerular basement membrane antibody positive glomerulonephritis; a case report

BackgroundThe prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD).Case presentationA 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient’s laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient’s renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits.ConclusionOn the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor.

P0358HYDROXYCHLOROQUINE PREVENTS ANTI-GBM GLOMERULONEPHRITIS IN RATS

Abstract Background and Aims Anti-glomerular basement membrane (GBM) glomerulonephritis (GN), characterized by glomerular crescent formation, requires early treatment because of poor prognosis. Hydroxychloroquine (HCQ) is a well-known antimalarial drug. In addition, it has immunomodulatory, anti-inflammatory, and autophagy inhibitory effects and its recognized in the treatment of autoimmune disease such as SLE. However, its effect for anti-GBM GN is unknown. In this study, we investigated the effect of HCQ against anti-GBM GN in rats. Method 7 week old male, WKY rats were induced by the administration of anti-GBM serum (50μg/rat). We administered either HCQ (50mg/kg) or vehicle (Phosphate-buffered saline) from day 0 to day 7 after the induction of nephritis. Renal function was assessed by measuring serum creatinine, proteinuria, hematuria. Urine was collected for 24 hours on day 1, 3, 5, and 7. Rats were sacrificed on day 7 after induction of anti-GBM GN. Renal histological changes were assessed by PAS staining, and Masson trichrome stain, and macrophage was assessed by ED-1 stain. Mitogen-Activated Protein Kinase (MAPK) was evaluated by western blotting (WB) and inflammatory cytokines were evaluated by ELISA using urine. Results HCQ treatment suppressed renal function decline. Histologically, extracellular and intracellular cells were increased from day 1, fibrinoid necrosis and ED-1 positive cells were observed from day 3. Rats with anti-GBM GN had high levels of interferon-α, interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α. These changes were significantly suppressed by HCQ. In addition, HCQ suppressed phosphorylation of JNK/p38 MAPK. Conclusion Our study showed that HCQ could attenuate anti-GBM GN and have an anti-inflammatory effect by inhibiting JNK/p38 MAPK activation. HCQ may have therapeutic potential in anti-GBM GN.

SAT-410 Clinicopathologic Features and Outcomes of Patients with Crescentic Glomerulonephritis with Renal Involvement: A Single-Center, 13-year Retrospective Study from Turkey

Crescentic glomerulonephritis (GN) is a group of the disease spectrum characterized by the presence of glomerular crescent formation as the principal histologic finding. We aimed to investigate the etiologic distribution and clinicopathologic features of the patients with biopsy-proven crescentic GN in the last 13 years in our center according to different percentages of crescents. Patients who had renal biopsy-proven glomerular crescent formation and recorded from 2005 to 2018 were retrospectively reviewed. The baseline clinical and laboratory parameters of all patients were obtained at the time of renal biopsy. Renal histopathological data were reviewed by light and immunofluorescence microscopy. According to the percentages of crescentic glomeruli, the patients were divided into three subgroups: group I (crescents <10%), group II (10%≤ crescents ≤30%) and group III (crescents >30%). The clinical, laboratory and histopathological features of patients, risk factors and outcomes were compared among the three groups. A total of 103 patients with biopsy-proven crescentic GN were included in the analysis and followed up. The results according to different percentages of crescents are presented in Table. As the percentage of crescentic glomeruli increased, it was associated with increased levels of baseline serum creatinine (p=0.018), lower baseline estimated glomerular filtration rate (eGFR) (p=0.002) and decreased macroscopic hematuria (p=0.032). In last outpatient clinic visit, eGFR, serum albumin and amounts of proteinuria were not different among the groups (p=0.096). The most common renal biopsy indications were rapidly progressive glomerulonephritis and nephrotic syndrome in all three groups (p=0.031). The disease spectrum of crescentic GN was as follows: 6 (6%) had anti-GBM GN, 16 (15.5%) had lupus nephritis, 27 (26%) had IgA nephropathy, 3 (3%) had infection-related GN, 5 (5%) had membranoproliferative GN, 42 (40.5%) had pauci-immune GN and 4 (4%) had others. There were no significant differences in the histological findings among the three groups except for mesangial cell proliferation and matrix expansion (p=0.002). Twenty three patients (%22.3) required dialysis on admission, including 6 (15%) patients with group II and 17 (36%) patients with group III (p<0.01). By the end of the follow-up period of 30 months, 35 (34%) patients progressed to end-stage renal disease (ESRD), requiring renal replacement therapy (7 (7%) renal transplantation and 28 (27%) dialysis) and 14 (13.5%) patients died. Cox regression analysis for renal survival showed that serum creatinine levels of 3.5 mg/dl or greater (HR= 1.5, 95% CI: 1.9-10.5, p<0.001) on admission and presence of interstitial fibrosis and tubular atrophy score >25% (HR= 2.7, 95% CI: 2-113, p=0.008) on renal biopsy were risk factors for ESRD. Of the etiologic spectrum of crescentic GN, pauci-immune GN had the poor renal and patient outcomes. This study provides valuable information about the disease spectrum of crescentic GN in our country. In patients with crescentic GN who present with different clinical features, an accurate and early diagnosis is essential for both renal and patient survival. Prognosis mostly depends on the degree of renal failure, histopathologic findings and the type of crescentic GN. Studies with larger sample sizes, including national registry data is still needed.

Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases.

Antiglomerular basement membrane disease manifests as rapidly progressive glomerulonephritis and alveolar hemorrhage. It encompasses 10-15% of crescentic glomerulonephritis and is associated with poor outcome. In this study, we have elaborated on the clinical details, morphological features, and outcome of anti-GBM glomerulonephritis. All the consecutive biopsy-proven cases of anti-GBM glomerulonephritis over a period of 4½ years were analyzed, retrospectively. Sixteen cases were diagnosed as anti-GBM glomerulonephritis during the study period. Twelve patients presented with rapidly progressive renal failure of which four patients required hemodialysis at the time of presentation. Goodpasture's syndrome was noted in two patients. Thirteen cases were positive for circulating anti-GBM antibodies and two patients showed double positivity for both anti-GBM antibodies and ANCA. Fifteen biopsies revealed crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane in all the 16 cases. Renal biopsy analysis is important in the diagnosis of Anti GBM nephritis. Morphology is an important predictor of disease progression.

A rare occurrence of anti-glomerular basement membrane glomerulonephritis complicated by heparin-induced thrombocytopenia

Introduction: Anti-glomerular basement membrane (GBM) disease is a rare condition that often presents as severe glomerulonephritis and pulmonary hemorrhage. Heparin-induced thrombocytopenia (HIT) is a well-known but uncommon complication of heparin exposure that is characterized by autoantibodies against platelet factor 4 (PF4)/heparin complexes. Although these conditions are well described in the literature, the coexistence of HIT and anti-GBM glomerulonephritis is extremely rare.

A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis.

In Goodpasture disease, the noncollagenous domain 1 of the α3 chain (α3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (α3127-148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in α1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN. We synthesized a modified peptide, replacing a single amino acid, and injected it into α3-P14-immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control. The modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide-treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced α3-P14-specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of α3-P14 to antibodies and MHC II molecules. A modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease.

A Case of Anti-Glomerular Basement Membrane Crescentic Glomerulonephritis in a Female Renal Allograft Recipient with Unknown Native Disease: Retrospective Molecular Confirmation of Alport Disease

Anti-Glomerular Basement Membrane (anti-GBM) crescentic glomerulonephritis developing in an allograft is a rare phenomenon. A patient with Alport syndrome receiving a renal transplant is at risk of developing anti-GBM glomerulonephritis, due to the absence of normal COL4α3, COL4α4 and COL4α5 trimer of the collagen network. Two unique challenges with planning kidney transplant in such a patient include- ideal donor selection; and risk of developing anti-GBM nephritis. We report a case of post-transplant anti-GBM crescentic glomerulonephritis in a female recipient with unknown native kidney disease who was diagnosed with Alport disease when she presented with hematuria and proteinuria nearly 2 years postrenal transplant. Allograft outcome in our case was unfavourable, patient reaching end-stage kidney disease within 6-month of diagnosis. The patient remains on continuous ambulatory peritoneal dialysis and currently active on the deceased donor transplant waiting list.

SUN-007 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE AND MONOCLONAL IMMUNOGLOBULIN RENAL DAMAGE IN MALIGNANT B-CELL DISORDERS: REAL CLINICAL PRACTICE – WHAT IS BEYOND MONOCLONAL IMMUNOGLOBULIN AMYLOIDOSIS?

Monoclonal gammopathy of renal significance (MGRS) merges paraprotein-mediated renal disorders in patients who do not meet criteria for multiple myeloma (MM) and systemic lymphoma (SL). MGRS is driven by monoclonal immunoglobulin (MIg), secreted by small non-malignant B-cell clone. By definition, diagnosis of MGRS requires identification of MIg deposition on kidney biopsy. Spectrum of MGRS, beyond MIg related amyloidosis, includes various types of tubular and glomerular disorders with organized and non-organized MIg or fragments thereof deposition: light chain proximal tubulopathy (LCPT), crystal-storing histiocytosis, fibrillary glomerulonephritis (GN), type I cryoglobulinemic (Cryo) GN, immunotactiod GN, monoclonal immunoglobulin deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 GN. Membranous nephropathy (MN) and anti-glomerular basement (anti-GBM) GN have also been described. Same lesions may occur during symptomatic B-cell proliferation, however high tumor mass with massive paraprotein precipitation more often results in cast-nephropathy (CN) in MM, or in glomerular intracapillary deposition of MIgM in Waldenström’s macroglobulinemia (WM). We aimed to evaluate the spectrum of MGRS versus MM/SL associated paraprotein-induced renal damage in patients, treated in our unit in 1997-2017. We identified 168 patients with biopsy-proven paraprotein-induced kidney damage, underwent advanced hematologic evaluation. Patients with MIg amyloidosis were excluded from further analysis. Pathology study included light microscopy and immune staining in all cases, and electron microscopy in 19% of cases. Study group included 41 patients, M/F 20/21, median age 61 [30; 76] years. Indications for kidney biopsy were nephrotic syndrome in 6 (14.6%), decline of kidney function in 17 (41.4%), or both in 18 (43.9%) of cases. Clinical diagnosis and pathology are shown in the Table 1. Tabled 1Clinical setting/Pathology patternMGRS 14 (34.1%)MM 20 (48.7%)WM 6 (14.6%)B-cell lymphoma 1 (2.4%)TotalMIDD10818PGNMID213MN22CN77LCPT33CN+LCPT11CN+MIDD22LCPT+MIDD11Anti-GBM GN11Cryo GN11C3 GN112Intracapillary deposition of MIgM44Total14246145 Open table in a new tab Patients with MGRS presented mainly with MIDD with few cases of PGNMID and MN. Patients with MM demonstrated not only CN, but also LCPT and MIDD, and various combinations of these patterns, single cases of PGNMID and anti-GBM GN were also observed in the setting of MM. Patients with WM presented mainly, but not exclusively, with glomerular intracapillary deposition of MIgM, with single cases of Cryo GN and C3 GN. The only case of B-cell lymphoma showed C3 GN. And vice versa, LCDD and PGNMID patterns were found both in MGRS and MM, and only MN was found exclusively in MGRS setting. CN and LCPT or both and in combination with LCDD were characteristic for MM. C3 GN was found in WM and B-cell lymphoma, single cases of anti-GBM GN and Cryo GN were found in MM and WM respectively. We did not find fibrillary and immunotactoid GN in our case series, most likely because of lack of electron microscopy studies. Conditions like LCPT, LCDD, PGNMID, C3 GN and anti-GBM GN, attributed in the literature mostly to MGRS, are also seen in patients with overt malignant B-cell disorders, demanding advanced henatology evaluation. Dual patterns of renal damage are not that rare, reflecting biclonal nature of B-cell proliferation.

MON-021 IMMUNOHISTOLOGICAL SPECTRUM OF CRESCENTIC GLOMERLONEPHRITIS, A SINGLE CENTER STUDY IN BANGLADESH

Crescentic glomerulonephritis (GN) is defined as presence of crescents in >50% of glomeruli sampled for renal biopsy. This is a critical diagnosis with clinical implications that ideally is communicated to the referring physician immediately. There is limited data on the etiology, clinical and histopathological spectrum of crescentic glomerulonephritis (CrGN) in Bangladeshi population. All the crescentic glomerulonephritis diagnosed histologically at Armed Forces Institute of Pathology, Dhaka irrespective of age and sex are included in the study. The study duration was from January 2017 to June 2018. The renal biopsy samples were undergone H&E, PAS, Masson trichrome and Methanamine silver staining. For each case direct immunofluoresnece study was carried out for IgG, IgM, IgA, C3, C1q, Kappa and Lambda. Depending on clinical, biochemical, serological, histological and immunofluorescence evaluation crescentic glomerulonephritis was classified. During stipulated period 21 crescentic glomerulonephritis were diagnosed which comprises 2.56% out of total 819 non transplant renal core biopsy patients. Mean age was 27.238 +14.928 the largest age group (8/21) being paediatric age group (<16 yrs). The male female ratio was 0.75. The most common presentation was rapidly progressive glomerulonephritis (RPGN) (7/21), followed by generalized body swelling (6/21). On urine examination 19/21 patients had haematuria and 7/21 patients had massive proteinuria (>3.0 Gm/24 hrs). The mean serum creatinine level was 5.65 mg/dl (1.3 to 18.85 mg/dl). Serum C3 & C4 level was found low in 6/18 and 2/15 cases respectively. ANA was positive in 2/21 cases and among those 1 was anti dsDNA positive and labeled as systemic lupus erythematosus (SLE). Among 21 cases 01 could not be classified due to lack of glomerulus during direct immunofluorescence (DIF) study. Pauciimmune crescentic glomerulonephritis (PI-CGN) was 10 (50%), Immune complex mediated crescentic glomerulonephritis (IC-CGN) was 9 (45%) and anti glomerular basement membrane disease (anti GBM disease) was 01(5%). Among the PI-CGN, 5 (50%) were ANCA positive and 03 (30%) were ANCA negative, for other 02 PI-CGN cases ANCA report was not available. Among ANCA positive PI-CGN 01 had associated ANA positivity. Among IC-CGN, 02 were crescentic IgA, 01 was crescentic lupus nephritis, 01 was isolated C3 glomerulonephritis, 03 were membranoproliferative glomerulonephritis with diffuse crescent formation and rest 02 were IC-CGN of unknown reason. The glomerular crescents formation was 80.33% in PI-CGN while it was 61.82% among IC-CGN cases and 66.67% in anti GBM glomerulonephritis. Among IC-CGN, 4/9 (44.44%) cases needed dialysis on admission while 5/10 (50%) PI-CGN cases were managed during admission by dialysis. The only anti GBM disease was tried to be managed by frequent dialysis but failed and plasmapheresis was advised but could not be instituted who ultimately succumbed to death following severe haemoptysis. In our study commonest cause of crescentic glomerulonephritis was pauci-immune crescentic glomerulonephritis followed by immune complex mediated glomerulonephritis. While one case of anti GBM glomerulonephritis was found that was possibly a case of Good pasture syndrome.

Standardized classification and reporting of glomerulonephritis

A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner. Translation by D.A. Mayer, T.O. Muzhetckaya, A.O. Mukhametdinova, M.S. Khrabrova.

Group 1 innate lymphoid cells are involved in the progression of experimental anti-glomerular basement membrane glomerulonephritis and are regulated by peroxisome proliferator-activated receptor α

Innate lymphoid cells play an important role in the early effector cytokine-mediated response. In Wistar Kyoto rats, CD8+ non-T lymphocytes (CD8+Lym) infiltrate into glomeruli during the development of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Here, we examined the profiles and roles of CD8+Lym in anti-GBM glomerulonephritis. The regulation of CD8+Lym by peroxisome proliferator-activated receptor (PPAR)-α in anti-GBM glomerulonephritis was also evaluated. Glomerular infiltrating CD8+Lym were lineage-negative cells that showed markedly high expression of IFN-γ and T-bet mRNAs but not Eomes, indicating these cells are group 1 innate lymphoid cells. In anti-GBM glomerulonephritis, the glomerular mRNAs of innate lymphoid cell-related cytokines (IFN-γ and TNF-α) and chemokines (CXCL9, CXCL10, and CXCL11) are significantly increased. Treatment with a PPARα agonist ameliorated renal injury, with reduced expression of these mRNAs. Invitro, enhanced IFN-γ production from innate lymphoid cells upon IL-12 and IL-18 stimulation was reduced by the PPARα agonist. Moreover, CXCL9 mRNA in glomerular endothelial cells and CXCL9, CXCL10, and CXCL11 mRNAs in podocytes and macrophages were upregulated by IFN-γ, whereas the PPARα agonist downregulated their expression. We also detected the infiltration of innate lymphoid cells into glomeruli in human anti-GBM glomerulonephritis. Thus, innate lymphoid cells are involved in the progression of anti-GBM glomerulonephritis and regulated directly or indirectly by PPARα. Our findings suggest that innate lymphoid cells could serve as novel therapeutic targets for anti-GBM glomerulonephritis.

HLA-DR15-specific inhibition attenuates autoreactivity to the Goodpasture antigen

Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3135-145-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b−/- background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3135-145-specific immune responses and disease development. Mice treated prior to immunization with α3135-145 had reduced α3135-145-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.

Development of anti-glomerular basement membrane glomerulonephritis during the course of IgA nephropathy: a case report

BackgroundAnti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy. We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months.Case presentationA 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years. Serum creatinine level was normal at that time. The first renal biopsy was performed. Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus. Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium. Therefore, the diagnosis was IgA nephropathy. Eight months later, the patient’s serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/gCr). The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL. Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy. At 4 weeks after admission, the second renal biopsy was performed. Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli. IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition. Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed. Renal function was not restored despite treatment, but alveolar hemorrhage was prevented.ConclusionsWe report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy. This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course.

Falsely positive anti-glomerular basement membrane antibodies in a patient with hantavirus induced acute kidney injury - a case report

BackgroundHantavirus infection is an uncommon cause of acute renal failure with massive proteinuria. Serology tests to support a presumptive diagnosis usually take a few days. During the initial work-up, autoimmune causes including anti-glomerular basement membrane (GBM) glomerulonephritis need to be excluded, because these require urgent therapy. In this case the delay in serological testing caused a dilemma in treatment initiation.Case presentationAn 18-year-old patient was admitted to the hospital with acute renal failure, erythrocyturia and massive proteinuria. Routine blood analysis showed leucocytosis (40,5 × 109/l) and a serum creatinine of 233 μmol/l. Infectious causes, e.g. leptospirosis or hantavirus infection, or an autoimmune disease, e.g., AAV or anti-GBM glomerulonephritis was the most feasible underlying diagnosis.Before hantavirus serology results were known, anti-GBM antibodies were positive. Treatment for anti-GBM glomerulonephritis was withheld, because of the absence of other signs and symptoms of the disease and slight improvement of renal function.The diagnosis of acute hantavirus infection was later on confirmed, by seroconversion of a follow-up serum sample. Without further intervention renal function recovered and anti-GBM antibodies disappeared.ConclusionHantavirus infection may induce anti-GBM antibodies, falsely suggestive of anti-GBM glomerulonephritis.Anti-GBM antibodies are supposed to be 100% specific. No earlier reports of false positive anti-GBM titers were reported. Nevertheless, the anti-GBM antibodies in this case were seen as an innocent bystander effect.Considering the need of urgent initiation of plasmapheresis and administration of immunosuppressants it may lead to diagnostic dilemmas with crucial therapeutic consequences. Knowledge of this anomaly when diagnosing acute renal failure, is very important.

Standardized classification and reporting of glomerulonephritis.

A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner.

Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar-Kyoto rats through anti-inflammatory effects.

Since recombinant human soluble thrombomodulin (RH-TM) has anti-inflammatory properties through neutralizing high-mobility group box 1 protein (HMGB1), the protective effects of RH-TM were examined in anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in Wistar-Kyoto rats. Rats were injected with nephrotoxic serum (NTS) to induce anti-GBM GN on Day 0, and were given either RH-TM or vehicle from Day 0 to Day 6. Rats were sacrificed 7 days after NTS injection. RH-TM-treated rats had decreased proteinuria and serum creatinine level. RH-TM significantly reduced the percentage of glomeruli with crescentic features and fibrinoid necrosis. In addition, RH-TM-treated rats had significantly reduced glomerular ED1+ macrophage accumulation as well as reduced renal cortical proinflammatory cytokine expression. Furthermore, RH-TM had a potent effect in reducing intercellular adhesion molecule-1 (ICAM-1) expression in kidneys and urine. RH-TM significantly reduced renal cortical mRNA levels for toll-like receptor -2 and -4, known as receptors for HMGB1, and their downstream adopter protein, myeloid differentiation primary respond protein 88 (MyD88). We showed for the first time that anti-inflammatory effects, which were characterized by reduced glomerular macrophage influx concomitant with a marked reduction in proinflammatory cytokines, were involved in the mechanism of attenuating experimental anti-GBM GN by RH-TM. The observed effects might be attributable to the downregulation of ICAM-1 by reducing the HMGB1/TLR/MyD88 signaling pathway.