Search

We present a 61-year-old male with FLT3-mutated acute myeloid leukemia treated with midostaurin who developed acute kidney injury requiring hemodialysis and pulmonary renal syndrome. Antibodies to proteinase-3, myeloperoxidase, and glomerular basement membrane were negative. Renal biopsy confirmed acute pauci-immune focal necrotizing glomerulonephritis (GN) with fibrin crescents indicating rapidly progressing glomerulonephritis. He improved with pulse methylprednisolone, intravenous cyclophosphamide, and plasma exchange with resolution of hemoptysis. This case highlights the importance of prompt renal biopsy to guide early initiation of life-saving therapies. To our knowledge, this is the first reported case of ANCA-negative pauci-immune necrotizing GN likely secondary to midostaurin.

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO)-ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci-immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides is an important cause of rapidly progressive glomerulonephritides (RPGN), and they are classically described as pauci-immune diseases as evidenced by the absence of immune deposits on immunofluoresence microscopy of the kidney biopsy. We report two patients with RPGN, pulmonary-renal syndrome, positive ANCA serology and linear Immunoglobulin G (IgG) staining on glomerular basement membrane in the absence of detectable anti-glomerular basement membrane (anti-GBM) antibodies in the serum.

A 15-year-old boy is admitted to the hospital for clinical signs that suggest a pulmonary-renal syndrome (fever, cough, hemopthoic expectoration, oliguria, gross hematuria). A crescentic pANCA positive glomerulonephritis was configured. However, dense subendothelial deposits were identified in electronic microscopy and immunofluorescence staining showed granular deposits of IgG and C3, kappa and lambda in the capillary loops. Although the treatment was strictly followed, after three years and three months of good clinical state, he manifested signs of kidney failure being transplanted. His case represents a specific pattern of rapidly progressive glomerulonephritis leading to kidney failure and emphasizes the importance of clinical attendance especially in a case of two associated glomerulopathies.

Background: Pulmonary-renal syndrome associated with anti-glomerular basement membrane (GBM) antibodies, also known as Goodpasture's syndrome, is a rare but acute and life-threatening condition. One third of patients presenting as anti-GBM antibody positive pulmonary-renal syndrome or rapidly progressive glomerulonephritis are also tested positive for anti-neutrophil cytoplasmic antibodies (ANCA). Whilst anti-GBM disease is considered a non-relapsing condition, the long-term course of double-positive patients is less predictable., Case Presentation: We report a patient with such dual positivity, who presented with pulmonary hemorrhage, crescentic glomerulonephritis and membranous nephropathy. Plasmapheresis in combination with immunosuppressive therapy led to a rapid remission but the disease relapsed after two years. The serum of the patient was tested positive for antibodies to human lysosomal membrane protein 2 (hLAMP2), a novel autoantigen in patients with active small-vessel vasculitis (SVV). The anti-hLAMP2 antibody levels correlated positively with clinical disease activity in this patient., Conclusion: We hypothesize that this antibody may indicate a clinical course similar to ANCA-associated vasculitis in double-positive patients. However, this needs to be confirmed on comprehensive patient cohorts.

Vasculitides that affect the lung represent a diverse group of diseases with various systemic clinical manifestations, and include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Churg-Strauss syndrome (CSS), and anti-glomerular basement membrane (anti-GBM) disease (Goodpasture syndrome). The etiologies of these diseases remain largely unknown. Although the pathogenic mechanisms of each differ, these diseases overlap by the presence of anti-neutrophil cytoplasmic autoantibodies in the vast majority of patients with MPA and GPA, and a substantial minority of patients with CSS and anti-GBM disease. This article reviews the current understanding of the pathogenesis of these four disease entities., (© Thieme Medical Publishers.)

Background: Both myeloperoxidase-associated antineutrophil cytoplasmic antibody (MPO-ANCA) and antiglomerular basement membrane antibody (anti-GBM Ab) positivity have been demonstrated in patients with rapidly progressive glomerulonephritis (RPGN), either with or without pulmonary hemorrhage; however, the implications of these antibodies in such patients have not yet been elucidated. The cases with dual positive antibodies were studied clinically, serologically, and pathologically, and the implications of antibodies are discussed here., Patients and Methods: Four patients with prior pulmonary fibrosis, who subsequently developed RPGN and pulmonary hemorrhage, were studied clinically, serologically, and pathologically. The clinical data were reviewed extensively and the dual positive antibodies were detected by enzyme-linked immunosorbent assays. Pathological studies were performed with a renal biopsy in one patient, a gastric biopsy in another patient, and autopsy materials in the remaining 2 patients., Results: All 4 patients had prior pulmonary fibrosis before the symptoms of RPGN when the dual positivity of MPO-ANCA and anti-GBM Ab was detected. Three cases were accompanied by pulmonary hemorrhage around the time of RPGN whereas the remaining case demonstrated pulmonary hemorrhage a few years later. Renal tissue specimens in 3 cases showed circumferential crescents and linear immunoglobulin G deposits along the glomerular capillary loops in glomeruli. Two autopsy specimens revealed vasculitis of the small arteries and arterioles of the kidney, and one of them showed similar vasculitic findings in both the gastrointestinal tract walls and the adipose tissues of the adrenal glands. Additionally, a case with pulmonary hemorrhage occurring after remission was associated with re-elevated MPO-ANCA levels but without anti-GBM Ab positivity. A gastric biopsy was unremarkable and non-contributory for the diagnosis, but this case showed vasculitic symptoms of peripheral neuritis and retinal hemorrhage. Taken together, all 4 cases demonstrated prior pulmonary fibrosis and dual positivity of MPO-ANCA as well as anti-GBM Abs at the time of RPGN, and were associated with either pulmonary hemorrhage or its occurrence thereafter., Conclusion: Four cases that showed prior pulmonary fibrosis as well as subsequent RPGN and pulmonary hemorrhage were both MPO-ANCA- and anti-GBM Ab-positive at the time of RPGN. The glomeruli disclosed features compatible with anti-GBM Ab disease, but the clinical and pathological vasculitic manifestations, including prior pulmonary fibrosis that might be an early manifestation of ANCA disease, suggested the occurrence of MPO-ANCA-associated vasculitis. Furthermore, 1 case subsequently showed repetitive pulmonary hemorrhage with re-elevated MPO-ANCA positivity but without anti-GBM Ab positivity, and this event was possibly due to MPO-ANCA-associated alveolar capillaritis. As anti-GBM Ab disease is generally thought not to manifest the clinical and pathological features of vasculitis excluding the kidney, MPO-ANCA might be a key factor regarding the occurrence of this dual positive disease.

Anti-glomerular basement membrane (GBM) antibody disease is clinically manifested as rapidly progressive glomerulonephritis (RPGN) with crescentic changes. The renal prognosis is poor. We report here the case of a 61-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive anti-GBM antibody disease. This patient was referred to our hospital because of RPGN. Anti-GBM antibody was positive with a titer of 38 EU. The MPO-ANCA titer was 65 EU. Chest imaging examination revealed pulmonary multiple nodules. ANCA-associated vasculitis was suspected. Renal pathology revealed cellular crescents in 13 out of 17 glomeruli. Immunofluorescence with anti-IgG antibody, anti-C3 antibody, and anti-fibrin antibody showed linear staining along the glomerular capillary walls. Based on these findings, the patient was diagnosed with anti-GBM antibody disease. Hemodialysis was started because of uremic syndrome with elevated serum creatinine (6.84 mg/dL). In addition, treatment with plasma exchange using 3.6 L (90 mL/kg) of fresh frozen plasma combined with an oral dose of 40 mg of prednisolone was initiated. Within 3 weeks, both types of autoantibodies became undetectable. Subsequently, this patient achieved dialysis independence and remission of glomerulonephritis. No adverse effects were observed. In patients with MPO-ANCA-positive anti-GBM antibody disease, intensive therapy predominantly with plasma exchange might be operative, even though renal function is less likely to recover.

The term pulmonary renal vasculitis syndrome describes a clinical syndrome of diffuse alveolar haemorrhage (DAH) complicating acute glomerulonephritis that often heralds severe, life-threatening systemic vasculitis requiring urgent, aggressive therapy. "Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis" and glomerular basement membrane ("Goodpasture's") disease are the commonest causes but other pathologies including systemic lupus erythematosus and the anti-phospholipid syndrome are also implicated. Such patients hence present most commonly to rheumatologists and nephrologists but usually require input from a number of specialties, respiratory and critical care medicine in particular. Such care is typically provided in specialist centres able to offer plasma exchange and experience in the use of immunosuppressants. We review clinical features, advances in therapy and understanding of pathophysiology., (2010 Elsevier B.V. All rights reserved.)

We describe a case of pulmonary-renal syndrome on autoimmune basis, with alveolar hemorrhage and worsening renal failure. The patient was positive for anti-MPO and anti-SCL/70. Immunosuppressive therapy was effective to treat the pulmonary condition, but chronic renal failure emerged. The clinical condition did not improve after plasmapheresis, thus chronic dialysis was required.

We report on a case of diffuse alveolar haemorrhage in a Chinese woman due to methimazole-induced antineutrophil cytoplasmic antibodies. A literature search for anti-thyroid drugs associated with antineutrophil cytoplasmic antibody-induced diffuse alveolar haemorrhages is reviewed. Diffuse alveolar haemorrhage is a rare complication of thiourea agents and the treatment often requires corticosteroids or other immunosuppressants, together with withdrawal of the causative agent.

Anti-myeloperoxidase (anti-MPO) antibodies have been implicated in the pathogenesis of small-vessel vasculitis, but the molecular mechanisms by which these antibodies contribute to disease are unknown. For determination of how anti-MPO antibodies affect inflammatory cell recruitment in small-vessel vasculitis, intravital microscopy was used to monitor leukocyte behavior in the accessible cremasteric microvessels under various experimental conditions. After local pretreatment of the cremaster muscle with cytokines (TNF-alpha, IL-1beta, or keratinocyte-derived chemokine), administration of anti-MPO IgG to wild-type mice reduced leukocyte rolling in favor of augmented adhesion to and transmigration across the endothelium. This led to a decrease in the number of systemic circulating leukocytes and, similar to the early events in the development of vasculitic lesions, an increase in leukocyte recruitment to renal and pulmonary tissue. TNF-alpha led to the greatest recruitment of inflammatory cells, and IL-1beta led to the least. When anti-CD18 was co-administered, anti-MPO IgG did not affect leukocyte rolling, adhesion, or transmigration; similarly, anti-MPO IgG did not produce these effects in Fc receptor gamma chain-/- mice. This study provides direct in vivo evidence of enhanced leukocyte-endothelial cell interactions in the presence of anti-MPO IgG and highlights the critical roles of Fcgamma receptors and beta2 integrins in mediating these interactions. In addition, it suggests that neutrophils primed by cytokines in the presence of anti-MPO IgG can have systemic effects and target specific vascular beds.

Benzylthiouracil has been recently observed to be associated with antineutrophil cytoplasmic antibody-positive vasculitis, resulting in crescentic glomerulonephritis. We report an 8-year-old girl treated with benzylthiouracil for Graves's disease who developed an ANCA-positive vasculitis with pulmonary hemorrhage. She responded to corticosteroids and discontinuation of benzylthiouracil. This represents the first pediatric case of benzylthiouracil-induced diffuse alveolar hemorrhage.

Despite clinical and experimental data suggesting a direct relationship between antineutrophil cytoplasmic antibodies (ANCAs) and disease activity in patients with microscopic polyangiitis (MPA), the causal relationship between perinuclear ANCAs specific for myeloperoxidase (MPO-ANCA) and disease manifestations has been controversial. We describe the case of a woman with a history of pulmonary-renal syndrome caused by MPA whose disease became clinically and serologically active during pregnancy. Forty-eight hours after delivery, the newborn developed pulmonary hemorrhage and abnormalities in renal function. The newborn's cord blood showed an immunoglobulin G MPO-ANCA level identical to that of the mother's serum, indicating passive transfer of the antibody to the neonate. Our findings represent the first human model supporting the interpretation that MPO-ANCAs were immunopathogenic.

A 57-year-old woman was admitted to our hospital because of severe dyspnea due to pulmonary hemorrhage and rapidly progressive renal failure. The patient was positive for perinuclear pattern anti-neutrophil cytoplasmic antibody (p-ANCA) and was manifested with gastrointestinal bleeding and brain hemorrhage. Thus, she was diagnosed as having microscopic polyangiitis (MPA). Laboratory examination demonstrated severe thrombocytopenia, increased prothrombin time and a high concentration of fibrin degradation products. In addition, the elevated plasma levels of D-dimer, thrombin-antithrombin complex and plasmin-plasmin inhibitor complex led us to make a diagnosis of disseminated intravascular coagulation (DIC). Complication of DIC was considered to have caused further deterioration in bleeding tendency due to MPA in the present case. The patient was treated with plasma exchange, hemodialysis, administration of corticosteroid including pulse therapy and cyclophosphamide. Continuous infusion of gabexate mesilate proved effective for improvement of systemic bleeding tendency. However, she finally died of severe infectious diseases. In conclusion, it is suggested that ANCA-associated vasculitis could be accompanied by DIC and gabexate mesilate may be a useful therapeutic agent for these disorders.

Pulmonary haemorrhage is a severe complication of small-vessel vasculitis associated with antineutrophil cytoplasm antibodies (ANCA). The main pathologic finding is a pauci-immune capillaritis, although occasionally this lesion is not present. The differential diagnosis includes different diseases and therefore ANCA measurement is important. Two cases of pulmonary haemorrhage associated with ANCA in patients with a clinical picture suggesting small-vessel vasculitis is here reported and a review of the literature is made.

A 31-year-old man was referred to our hospital for the management of progressive diffuse alveolar hemorrhage associated with renal dysfunction. Leukocytoclastic vasculitis was shown by skin biopsy and crescentic glomerulonephritis was also detected, in addition to positivity for proteinase 3-specific anti-neutrophil cytoplasmic antibodies (PR3-ANCA). The patient was diagnosed as a rare case of PR3-ANCA-positive pulmonary-renal vasculitic syndrome without granulomatous lesions. There was a good response to combination therapy with steroids and cyclophosphamide.

Propylthiouracil (PTU) is known to cause vasculitis as a rare complication. We report the case of a patient who developed alveolar haemorrhage and haematuria whilst treated with PTU. The serum was positive for antineutrophil cytoplasmic antibody (ANCA) with myeloperoxidase (MPO) specificity (MPO-ANCA). All symptoms resolved completely after discontinuation of PTU. Alveolar haemorrhage or pulmonary-renal syndrome associated with antineutrophil cytoplasmic antibody with myeloperoxidase specificity may be a new complication of propylthiouracil therapy.