Clinical Profile, Treatment Outcomes, and Complement Pathway Involvement in Idiopathic ANCA-negative Renal-Limited Pauci-immune Crescentic Glomerulonephritis: A Single-Centre Prospective Study

The Utility of Myeloperoxidase Immunostaining to Characterize Immune Deposits in Patients With Crescentic Glomerulonephritis

Background: Pauci-immune crescentic glomerulonephritis is the most common cause of crescentic glomerulonephritis (CrGN). Patients usually present with rapidly progressive glomerulonephritis (RPGN) with hematuria, proteinuria, and elevated serum creatinine levels. The characteristic feature of pauci-immune CrGN is focal necrotizing CrGN associated with little or no glomerular staining for immunoglobulin (Ig) by immunofluorescence microscopic examination. Most patients (80-85%) with pauci-immune CrGN, including the patients with and without systemic vasculitis, have antineutrophil cytoplasmic autoantibodies (ANCAs). Aims and Objectives: To study and compare the histological and laboratory features of ANCA-positive and ANCA-negative pauci-immune CrGN. Materials and Methods: Patients who were diagnosed with pauci-immune CrGN from January 2012 to May 2015, at BABINA Diagnostics, were included in this retrospective study. The terms pauci-immune and crescentic glomerulonephritis were defined according to standard guidelines. The demographic and laboratory data were extracted from the Laboratory Information System (LIS) for analysis. ANCA tests were performed by both indirect immunofluorescence (IIF) assay (EUROIMMUN, Lubeck, Germany) and antigen-specific enzyme-linked immunosorbent assay (ELISA) (ORGENTEC Diagnostika GmbH, Germany). Renal specimens were evaluated using direct immunofluorescence (for Ig and complement components) and light microscopy using routine and special stains. Results: Four (19%) out of the 21 cases of pauci-immune CrGN were ANCA negative. Acute features on histology were seen more than chronic features than ANCA-negative cases. Conclusion: Among the patients with pauci-immune CrGN, ANCA-negative patients were not rare. Compared with ANCA-positive patients, ANCA-negative patients had a lower percentage of normal glomeruli, more of chronic features, and a higher level of proteinuria.

Background: Pauci-immune crescentic glomerulonephritis (CrGN) is one of the most common etiologies of rapidly progressive glomerulonephritis. This condition presents with crescentic glomerulonephritis with little or no immunoglobulin staining and negative serological workup aside from a positive antineutrophil cytoplasmic autoantibody (ANCA). Typically, patients with pauci-immune CrGN have an underlying systemic small vessel vasculitis, but in rare cases, it presents without any known vasculitis or ANCA. Pauci-immune ANCA negative CrGN is often strictly isolated to the kidneys. In this case, we present a patient with ANCA negative, pauci-immune CrGN with severe diffuse alveolar hemorrhage.Case Presentation: A 66-year-old Hispanic woman with a past medical history of controlled hypertension presented with fatigue and dysphagia. On admission, her vital signs were significant for hypoxia on room air, and her physical exam was remarkable for crackles bilaterally. The initial laboratory results revealed anemia (hemoglobin 5.2 g/dL), hyperkalemia (6.3 mmol/L), elevated creatinine (4.50 mg/dL, with a baseline of 0.9mg/dL). Urinalysis showed moderate blood and urine protein (200 mg/dL). Urine microscopic examination showed 25-50 RBCs seen/high power field.The patient was admitted to ICU due to hypoxia, a computed tomography scan of the chest/abdomen/pelvis was obtained and revealed multifocal pulmonary consolidations. A blood transfusion was ordered. The patient began to have hemoptysis and subsequent bronchoscopy showed diffuse alveolar hemorrhage. ICU team proceeded to intubate her as the hemorrhage continued to worsen. Further workup revealed a positive anti-nuclear antibodies (ANA) of 1:40, but otherwise negative serologies including myeloperoxidase (MPO)-ANCA, glomerular basement membrane antibody, and anti-double stranded DNA. Kidney biopsy showed necrotizing glomerulonephritis with crescents and negative immunofluorescence. She was diagnosed with pauci-immune ANCA-negative vasculitis with associated diffuse alveolar hemorrhage and nephritis based on these results and was started on pulse-dose steroids. The patient was started on intravenous (IV) high-dose cyclophosphamide, which helped improved the overall clinical condition significantly. After creatinine began trending down and urine output improved, the patient was discharged on a regimen of daily oral cyclophosphamide and steroid taper. Patient oxygen requirements decreased and she was sent home with supplemental oxygen while requiring 3L/min of oxygen.Conclusion: Pauci-immune and ANCA-negative glomerulonephritis with concurrent diffuse alveolar hemorrhage is exceptionally rare. In this situation, medical management relied on clinical evidence from similar populations in the use of steroids and cyclophosphamide. This case report aims to shed more light on the clinical progression and management of this condition. Here we present a case of pulmonary-renal syndrome with biopsy-proven glomerulonephritis but without ANCA positive serologies.

To determine the etiology, course and predictors of outcome in children with crescentic glomerulonephritis (GN). Retrospective, descriptive study. Pediatric Nephrology Clinic at a referral center in Northern India. Clinic records of patients aged <18 year with crescentic GN diagnosed from 2001 - 2010 and followed at least 12 months were reviewed. Crescentic GN, defined as crescents in ≥50% glomeruli, was classified based on immunofluorescence findings and serology. Risk factors for renal loss (chronic kidney disease stage 4-5) were determined. Of 36 patients, (median age 10 yr) 17 had immune complex GN and 19 had pauci-immune crescentic GN. The etiologies of the former were lupus nephritis (n=4), postinfectious GN (3), and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II (2 each). Three patients with pauciimmune GN showed antineutrophil cytoplasmic antibodies (ANCA). Rapidly progressive GN was present in 33 patients, and required dialysis in 12. At median 34 (19-72) months, 2 patients with immune complex GN and 8 with pauciimmune GN showed renal loss. Renal survival was 94.1% at 3 yr, and 75.3% at 8 yr in immune complex GN; in pauciimmune GN survival was 63.2% and 54.1%, respectively (P=0.054). Risk factors for renal loss were oliguria at presentation (hazards ratio, HR 10.50; P=0.037) and need for dialysis (HR 6.33; P=0.024); there was inverse association with proportion of normal glomeruli (HR 0.91; P=0.042). Pauci-immune GN constitutes one-half of patients with crescentic GN at this center. Patients with pauciimmune GN, chiefly ANCA negative, show higher risk of disease progression. Renal loss is related to severity of initial presentation and extent of glomerular involvement.

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

A RARE CASE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-NEGATIVE PAUCI- IMMUNE FOCAL NECROTIZING AND CRESCENTIC GLOMERULONEPHRITIS PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

Crescentic glomerulonephritis (GN) is one of the common causes of rapidly progressive glomerulonephritis (RPGN). Pauci-immune crescentic GN is usually associated with anti-neutrophil cytoplasmic antibody (ANCA). However, patients with pauci-immune crescentic GN who lack ANCAs have recently been reported. Approximately 10-30% of patients with pauci-immune crescentic GN lack ANCAs. The clinical characteristics of patients with ANCA-negative pauci-immune crescentic GN are not entirely the same as patients with ANCA-positive GN, and this suggests that ANCA-negative and ANCA-positive pauci-immune crescentic GN might be different disease entities. We report a patient with ANCA-negative crescentic GN complicated with multiple opportunistic infections (Candida albicans, herpes simplex virus, and Cytomegalovirus) in the digestive tract during the course of immunosuppressive therapy. After antifungal and antiviral therapies including itraconazole, valaciclovir, and ganciclovir, she recovered from multiple opportunistic infections. The occurrence of comorbid opportunistic infections during the course of immunosuppressive therapy may not be rare in the elderly. However, a case of multiple opportunistic infections limited to the digestive tract is very rare.

One of the most common causes of rapidly progressive glomerulonephritis (GN) is the so-called pauci-immune crescentic GN that is characterized by no luminescence in kidney tissue samples during immunofluorescence microscopy and by the hyperproduction of antineutrophil cytoplasmic antibodies (ANCA). At the same time, serum ANCAs are absent in a number of cases of pauci-immune GN. Based on their own experience, the authors present the clinical and morphological characteristics of patients with ANCA-negative pauci-immune GN and analyze the data available in the literature. Subjects and methods. This retrospective study included 8 patients with ANCA-negative pauci-immune GN, who were followed up at two Russian centers (the Center of Nephrology and the Center of Rheumatology) in 2011 to 2015. Results and discussion. According to our data, ANCAs are not detectable in 6% of the patients with ANCA-associated systemic vasculitis (SV) with renal involvement and/or pauci-immune GN. The mean age at onset of the disease in the ANCA-negative patients was 50±18 years (range 19 to 74 years); the male/female ratio was 1:1. Four (50%) cases were diagnosed with microscopic polyangiitis; 2 cases had granulomatosis with polyangiitis; isolated renal injury was present in other 2 patients. The Birmingham SV activity index averaged 19.6±7.9. Hematuria was observed in all cases and it was massive in 4. The mean daily urinary protein level was 3.4±2.7 g; three (38%) patients were observed to have nephrotic syndrome. The blood creatinine level averaged 704±405 μmol/l; GN was characterized by a rapidly progressive course in 6 (75%) patients; hemodialysis was needed in 5. A morphological study of the kidney determined crescents (in on an average of 52 glomeruli) in the majority of cases and glomerulosclerosis in one patient. All the patients were observed to have varying degrees of interstitial fibrosis. Three (38%) treated patients achieved remission. The mortality rates were 38%. Interestingly, the data from our group as well those obtained by the study of European cohorts were slightly different from those of the studies conducted in Asia, according to which a renal biopsy more frequently revealed glomerular crescents; the levels of protein in the urine were higher and renal survival was worse. Thus, serum ANCAs are absent in 3–39% of cases of pauci-immune crescentic GN, but the clinical and morphological picture corresponds to ANCA-associated SV. A kidney biopsy helps establish the correct diagnosis, timely use induction treatment, and improve prognosis.

BackgroundCrescentic glomerulonephritis is a disease characterized by severe glomerular injuries that is classified into five different pathological types. Patients with type V disease have pauci-immune crescentic glomerulonephritis (PICGN) that is negative for anti-neutrophil cytoplasmic autoantibodies (ANCAs). There are limited clinical data on the manifestations, treatment, and prognosis of type V crescentic glomerulonephritis, especially in children.Case presentationA 13-year-old girl who had an intermittent fever for more than 10 months was admitted to our hospital. She had no gross hematuria, oliguria, edema, or hypertension, but further tests indicated a decreased glomerular filtration rate, hematuria, proteinuria, and an elevated level of IL-6. The antinuclear antibody spectrum test was positive at 1:1000, and the ANCA and anti-glomerular basement membrane antibody tests were negative. A renal biopsy confirmed the diagnosis of ANCA-negative PICGN. We administered methylprednisolone pulse therapy with intravenous cyclophosphamide and oral mycophenolate mofetil. At the 3-month follow-up, her urine protein level was significantly lower, and her serum creatinine level was in the normal range.ConclusionsFever may be an extrarenal manifestation of ANCA-negative PICGN, and IL-6 may play a role in the pathogenesis of this disease. Early methylprednisolone pulse therapy with an immunosuppressant may reduce symptoms and improve prognosis.

Circulating anti-neutrophil cytoplasmic antibodies (ANCA) have been described in most patients with "pauci-immune" necrotizing and crescentic glomerulonephritis. A 29-kDa serine protease (p29 or proteinase 3) and myeloperoxidase are the two best characterized antigens recognized by ANCA. The study presented here was conducted to define the diagnostic value of assays for antibodies against these two antigens in rapidly progressive glomerulonephritis. Radioimmunoassays were developed for anti-p29 and anti-myeloperoxidase antibodies, with purified antigens, and the results of the radioimmunoassays were compared with those obtained by immunofluorescence tests for ANCA. We performed assays on serum samples from 123 patients with the syndrome of rapidly progressive glomerulonephritis, as well as from 200 blood bank donors and from 717 additional control patients. Without knowledge of the results of ANCA tests, the renal pathologic findings in the 123 patients with rapidly progressive glomerulonephritis were analyzed, and 42 were classified as pauci-immune necrotizing and crescentic glomerulonephritis, 18 were classified as anti-glomerular basement membrane nephritis and 63 were classified as other forms of renal disease. We found radioimmunoassays to be more reliable in the diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis than immunofluorescence testing. By radioimmunoassay, ANCA were found in 40 of 42 patients (95% sensitivity) with pauci-immune necrotizing and crescentic glomerulonephritis (14 with anti-p29 and 26 with anti-myeloperoxidase antibodies). The tests for antibodies to p29 and myeloperoxidase were 99.9 and 99.5% specific for pauci-immune necrotizing and crescentic glomerulonephritis, respectively. In the setting of rapidly progressive glomerulonephritis, a positive radioimmunoassay for anti-p29 or anti-myeloperoxidase antibodies (together with a negative test for anti-GBM antibodies) gives a probability of pauci-immune necrotizing and crescentic glomerulonephritis of over 99%.

To prevent the spread of the coronavirus disease 2019 (COVID-19) pandemic, vaccines have been authorized for emergency use and implemented worldwide. We present a case of de novo glomerulonephritis (GN) after use of the COVID-19 mRNA vaccine BNT162b2. A 48-year-old man with no relevant medical history was referred for sudden and persistent worsening of renal insufficiency 1.5 months after the second vaccine dose. He had arthralgia and skin rash a week after vaccination. Abdominal pain and diarrhea started 2 weeks later, and he was admitted to the hospital for enteritis treatment. Colonoscopy showed multiple ulcerations and petechiae suggestive of vasculitis in the terminal ileum. After prednisolone therapy, his gastrointestinal symptoms improved, but his renal function continued to deteriorate. Based on kidney biopsy findings and nephrotic-range proteinuria (5,306 mg/24 hours), he was diagnosed with anti-neutrophil cytoplasmic autoantibody (ANCA)-negative pauci-immune crescentic GN (CrGN). He received high-dose steroid pulse therapy and oral cyclophosphamide, and then, gradually underwent steroid tapering, with improvement in proteinuria and renal function over several weeks. Several cases of GN suspected to be related to COVID-19 vaccines have been reported. To our knowledge, this is the first case report of ANCA-negative pauci-immune crescentic CrGN with extrarenal involvement after COVID-19 mRNA vaccination. Our finding expands the spectrum of COVID-19 vaccine-associated GN.

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury. In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokine-primed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Anti-idiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodies in vitro, in a V region-dependent manner, are found in pooled human gamma-globulin preparation. Intravenous immune globulin infusions in vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab')2-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitely intravenous immune globulin as a therapeutic option in vasculitic disorders.

Poor Renal Outcome of Antineutrophil Cytoplasmic Antibody Negative Pauci-immune Glomerulonephritis in Taiwanese

Renal involvement in systemic lupus erythematosus (SLE) is usually immune complex mediated and may have multiple different presentations. Pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) refers to extensive glomerular inflammation with few or no immune deposits that may result in rapid decline in renal function. We report a case of a 79-year-old Hispanic male with a history of secondary membranous nephropathy (diagnosed by renal biopsy 15 years previously) who was admitted with acute kidney injury and active urinary sediment. P-ANCA titers and anti-myeloperoxidase antibodies were positive. The renal biopsy was diagnostic for NCGN superimposed on a secondary membranous nephropathy. A previous diagnosis of SLE based on American College of Rheumatology criteria was discovered via Veteran's Administration records review after the completion of treatment for pauci-immune NCGN. ANCAs are detected in 20–31% of patients with SLE. There may be an association between SLE and ANCA seropositivity. In patients with lupus nephritis and biopsy findings of necrotizing and crescentic glomerulonephritis, without significant immune complex deposition, ANCA testing should be performed. In patients with secondary membranous nephropathy SLE should be excluded.

Crescentic glomerulonephritis (GN) without immune reactants or deposits (referred to as pauci-immune) is typically characterized by the presence of anti-neutrophilic cytoplasmic antibodies (ANCA). While ANCA-negative patients might be expected to have a more benign course, they often have poor renal outcomes, especially without treatment with steroids and immune-modulating therapy. Pauci-immune crescentic GN can also co-exist with other autoimmune conditions, including rheumatoid arthritis (RA). Here, we describe an ANCA-negative patient with RA who developed dialysis-requiring acute kidney injury (AKI) with findings consistent with focal pauci-immune crescentic GN (i.e., no IgG or immune complex on kidney biopsy). Coexistent conditions included Klebsiella sepsis attributed to pneumonia, rhabdomyolysis, leukocytoclastic immune-mediated skin vasculitis, and positive ANA. He had spontaneous improvement in renal function without immunosuppressive therapy. This crescentic GN was not associated with poor renal outcome as AKI resolved with supportive care and treatment of his infection. The AKI was likely multifactorial with co-existing acute tubular necrosis in the setting of Kebsiella sepsis and rhabdomyolysis, and the crescentic GN was felt more likely to be related to the infection rather than having a primary role. This case highlights the importance of viewing crescentic GN in the context of the clinical picture, as it may not always lead to the need of aggressive immune suppression and is not a universally poor prognostic kidney finding. However, these cases do warrant close follow-up as our patient had recurrent RA disease manifestations over the next 2 years that eventually led to his death from severe pulmonary hypertension.