Pauci-immune Glomerulonephritis Research Articles

A case of a 6-year-old girl with anti-neutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis

A 6-year-old girl was admitted to our hospital with proteinuria, hematuria, skin rash and joint pain of the lower limbs. Due to rapid progression of renal insufficiency, hemodialysis and peritoneal dialysis were performed. She was diagnosed with rapidly progressive glomerulonephritis. Kidney biopsy showed severe crescent formation (50% of glomeruli) and no deposition of any immunoglobulins or complements. Serologically, anti-neutrophil cytoplasmic autoantibody (ANCA) was negative not only by ELISA against proteinase-3 and myeloperoxidase-ANCA but also by indirect immunofluorescent assay against cytoplasmic and perinuclear ANCA. Anti-glomerular basement membrane antibody was also negative. In the acute phase, proinflammatory cytokines such as soluble tumor necrosis factor receptor 1 (sTNFR1), soluble interleukin (IL)-2 receptor (sIL2R), IL-6 and chemokine IL-8 were elevated. The patient was diagnosed with ANCA-negative pauci-immune crescentic glomerulonephritis (CrGN). Intensive treatment with methylprednisolone pulse therapy, plasma exchange, and multiple drug therapy including prednisolone and cyclophosphamide resulted in histopathological improvement and complete remission of proteinuria. There was a possibility that sTNFR1, sIL2R, IL-6 and IL-8 might be involved in the initiation and progression of ANCA-negative pauci-immune CrGN, and to remove and suppress these cytokines might be an effective way to treat ANCA-negative pauci-immune CrGN.

Impact of Immunofluorescence on the Histological Pattern of Pediatric Kidney Biopsies from Northern Pakistan

Kidney biopsy is an investigation for diagnosis and prognosis of a variety of nephritides. It also influences therapeutic options. Immunofluorescence (IMF) greatly adds in identifying the pathologies which may not be obvious on light microscopy (L/M), such as IgM, IgA nephropathy, pauci-immune glomerulonephritis, and anti-glomerular basement membrane disease. We present here data of 170 pediatric kidney biopsies from July 2005 to December 2009 from Department of Nephrology and Hypertension, Lady Reading Hospital, Peshawar, Pakistan. The study was undertaken to see whether IMF would alter the histological pattern of pediatric kidney biopsies and to compare these data with an earlier data from our department of 415 pediatric kidney biopsies done over 7-year period from 1998 to 2005, which were analyzed with L/M alone. Out of 170 kidney biopsies using L/M and IMF, IgM turns out to be most common pattern (20%), followed by minimal change disease (MCD) (17.05%), focal and segmental glomerulosclerosis (FSGS) (15.88%), chronic sclerosing glomerulonephritis (Chr. sclerosing GN) (12.35%), mesangio proliferative glomerulonephritis (MPGN) (7.65%), mesangio capillary glomerulonephritis (MCGN) (6.47%), membranous glomerulonephritis (Mem. GN) (5.29%), IgA nephropathy (5.29%), cresentic glomerulonephritis (Cres. GN) (3.53%), lupus nephritis (2.96%), and others (3.53%). Comparing these results of 170 cases with 415 renal biopsies without IMF, IgM dominated the histological pattern in IMF group whereas MCD followed by FSGS and MPGN were prominent in group without IMF. Therefore, variation in the overall histological pattern with IMF technique proved statistically significant (p < 0.0001). Addition of IMF has altered the frequency of MCD, a change from 24% (100/415) to 17% (29/170), FSGS from 18.3% (76/415) to 15.88% (27/170), and MPGN from 17.35% (72/415) to 7.65% (13/170).

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.

Anti-neutrophil Cytoplasmic Antibody-associated Pauci-immune Crescentic Glomerulonephritis Complicating Sjögren's Syndrome

Sjögren's syndrome is a chronic autoimmune disease, characterized by specific autoimmune antibodies anti-Ro and anti-La, and it can involve multiple organs, such as the kidneys, lungs, muscles, and nervous system. The most common renal complication of Sjögren's syndrome is tubulointerstitial nephritis, and glomerulonephritis is relatively uncommon. We report the case of an 86-year-old man presenting with recurrent fever, poor appetite, decreased salivary secretion, and body weight loss. Laboratory investigation revealed that serum creatinine was 4.2 mg/dL, proteinuria was 3+, and there was microscopic hematuria. Positive perinuclear anti-neutrophil cytoplasmic antibody, anti-Ro, and anti-La antibodies were detected. Renal biopsy showed crescentic glomerulonephritis with scanty immune complex deposition. The patient was diagnosed with primary Sjögren's syndrome complicated with rapidly progressive glomerulonephritis with positive anti-neutrophil cytoplasmic antibody. Unlike the patients of other case reports, our patient's renal function did not recover after immunosuppressant treatment, and he finally received long-term hemodialysis. Pauci-immune glomerulonephritis is a rare renal complication of Sjögren's syndrome, and progress to renal failure in such patients is possible.

A case of psoriasis with ANCA-negative pauci-immune crescentic glomerulonephritis in children

A case of psoriasis with ANCA-negative pauci-immune crescentic glomerulonephritis in children

Diagnosis of IgG4-Related Tubulointerstitial Nephritis

IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell-rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell-rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90-100%) and a specificity of 92% (95% CI 86-95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.

Renal histology in the elderly: indications and outcomes

Renal disease is being increasingly diagnosed in the elderly. However, reports on biopsy-confirmed renal disease in this population are limited. The aim of this study was to give an overview of the most important indications, diagnoses and outcomes of renal biopsies in the elderly in our center. This was a retrospective review of all elderly renal biopsies over 5 years. Patients were eligible for inclusion if they were aged ≥65 years and had had a native kidney biopsy performed. The data recorded included age, sex, indications for biopsy, histological diagnoses and outcomes. During this time, 1,372 native renal biopsies were performed. Of these, 236 (17%) were in patients aged ≥65 years; 150 male (64%) and 86 female (36%). The most common indications for biopsy were acute renal failure and nephrotic syndrome. Common diagnoses included pauci-immune crescentic glomerulonephritis, tubulointerstitial nephritis, membranous nephropathy, IgA nephropathy and chronic thrombotic microangiopathy. Long-term follow-up of 3 years was available for 102 patients; median serum creatinine at the time of biopsy was 427 µmol/L (interquartile range 204-702) and at 3 years post biopsy had fallen to 192 µmol/L (interquartile range 152-408). In our center, 17% of native kidney biopsies are performed in elderly patients aged ≥65 years. In our experience, this procedure was safe and had a 97% diagnostic rate. The available follow-up data of patients suggest that renal histology is not only of benefit in diagnosis but also of potential value in terms of prognosis and treatment.

Glomerulonephritis with crescents among adult Saudi patients outcome and its predictors

The aim of this study is to investigate the clinical and pathological features and outcome of glomerulonephritis with crescents among adult patients. This is a retrospective study of all cases of crescentic GN seen over a 9-year period (2001-2010). Histological features were assessed, and renal function at baseline and end of follow-up period was recorded. Results among different etiological groups at baseline and end of follow-up period were compared. The mean age in the whole group was 35.6years (16.2), with the lowest mean in the lupus nephritis (LN) group [27.7years (9.9)] and the highest in the pauciimmune glomerulonephritis (PIGN) group (P=0.001). There were 72 cases enrolled in the study. LN accounted for 49.3% of the cases, PIGN for 26.5%, other immune complex glomerulonephritis (ICGN) for 19% and post-infectious GN accounted for 6.3% The majority (85.7%) of the patients had renal impairment at presentation (mean serum creatinine levels were 247 (85)μmol/l, 412 (75)μmol/l and 230 (141)μmol/l in LN, PICN and ICGN, respectively (P=0.05). Women accounted for 85.3, 76.5 and 36.2% of the patients in LN, PICN and ICGN, respectively (P=0.025). By the end of the follow-up period of 26 (22.9) months, 25.8% of the patients were requiring dialysis (16.70% in the LN group, 50% in PIGN and 25% in ICGN (P=0.05) and 21.7% had nephrotic range proteinuria (16.7, 1 and 33.3%, respectively (P=0.4). Using logistic multivariate analysis, the only independent factors found to predict need for dialysis of prognosis were percent of sclerosed glomeruli (P=0.05) and presence of ATN (P=0.028). Baseline proteinuria or SCr, gender and number of glomeruli with crescents, on the other hand, did not impact prognosis. Using linear regression multivariate analysis, SCr, protein excretion and activity score at biopsy did not influence change in SCr or final SCr during the follow-up period. Using ANOVA to compare the groups of LN, PIGN and ICGN), we found significant differences only in gender between LN and ICGN (P=0.035), in percent glomerular global sclerosis (between LN and PIGN (P=0.007) and between LN and ICGN (P=0.012) and in age (between LN and PIGN (P=0.006). Almost half of our patients with CrGN were due to LN which is higher than that reported by others where PIGN was the more prevalent etiology. Patients with PICN were older and had worse prognosis. This could be explained by the higher number of globally sclerosed glomeruli in the PIGN group.

Antineutrophil cytoplasmic antibodies

Antineutrophil cytoplasmic antibodies (ANCA) are predominantly IgG autoantibodies directed against constituents of primary granules of neutrophils and monocytes lysosomes. Although several antigenic targets have been identified, those ANCA directed to proteinase 3 or myeloperoxidase are clinically relevant, whereas the importance of other ANCA remains unknown. Both are strongly associated with small vessel vasculitides, the ANCA-associated vasculitides, which include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, and the localised forms of these diseases (eg, pauci-immune necrotising and crescentic glomerulonephritis). ANCA is a useful serological test to assist in diagnosis of small-vessel vasculitides. 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. There is increasing evidence that myeloperoxidase-ANCA are directly involved in the pathogenesis of necrotizing vasculitis. This is less clear for proteinase 3-ANCA, markers for Wegener's granulomatosis. With respect to proteinase 3-ANCA, complementary proteinase 3, a peptide translated from the antisense DNA strand of proteinase 3 and homologous to several microbial peptides, may be involved in induction of proteinase 3-antineutrophil cytoplasmic autoantibodies.

Pauci-immune crescentic glomerulonephritis complicating Sjögren's syndrome in a 12-year-old girl

Dear Sirs,We read with great interest the article by Jung SK et al. onmesangial proliferative glomerulonephritis and IgA depos-its in a child with Sjogren's syndrome (SS) recentlypublished in Pediatric Nephrology[1]. The most commonform of renal involvement in SS is tubulointerstitialnephritis, generally causing mild renal dysfunction [2].Glomerulonephritis (GN) is rare with membranoprolifer-ative and membranous nephropathy being the mostcommonly described glomerular lesions, whereas cres-centic GN has been only occasionally reported in adults[3, 4]. Wefolloweda12-year-oldgirlwithprimarySS,whopresented with acute renal failure due to pauci-immunecrescentic GN with severe tubulointerstitial damage. Thepatient had a 7-year history of sicca syndrome withenlargement of both lacrimal glands and an abnormalSchirmer's test, pointing to the diagnosis of SS. At theage of 12 years, she presented with general malaise andthe biochemical signs of acute renal failure (creatinine9.5 mg/dl, BUN 103 mg/dl), oliguria (0.4 ml/kg/h),moderate proteinuria (1.23 g/l) and microscopic hematu-ria. Antistreptolysin O, anti-cardiolipin and lupus antico-agulant antibodies were absent. Viral serology (hepatitis Band C, HIV) was negative as well. Rheumatoid factor andC3, C4 complement levels were normal. Anti-DNAantibody titer measured by ELISA was 1:200. ANCA,ANA, and Anti-Ro/SS-A could be measured by immuno-fluorescence on the 90th day only. C-ANCA and p-ANCAwere negative, ANA titer (Hep-2) was 1:160 and Anti-Ro/SS-A were present (+).Renal biopsy contained 54 glomeruli, from which twowere completely sclerotic, four demonstrated fibrocellu-lar crescents, and all remaining glomeruli showed largecellular crescents (Fig. 1a). Tubulointerstitial inflamma-tion with patchy cellular infiltrates containing lympho-cytes, plasma cells, and monocytes was present (Fig.1b).Immunofluorescence with antibodies against IgG, IgA,IgM, C1q, C3, fibrinogen, κ and 1 light chains wasnegative.The patient received three pulses of methylprednisolone1,000 mg daily, followed by oral prednisolone 60 mg/day.Alternate-day plasmapheresis with substitution of 1 plasmavolume (x 4 times) and intravenous cyclophosphamidetreatment (750 mg/m

ANCA-associated glomerulonephritis in the very elderly

Antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune glomerulonephritis (GN) is the most common finding in very elderly patients biopsied for acute kidney injury. Appropriate treatment strategies in this age group are currently undefined since it is unclear whether the benefits of immunosuppression exceed the risks. We retrospectively evaluated a cohort of 78 cases of biopsy-proven pauci-immune GN in individuals aged >80 years of whom 72% were p-ANCA and 20% were c-ANCA positive. The patients treated with immunosuppression had a significantly lower incidence of end-stage renal disease (ESRD) 1 year after biopsy (36%) compared with untreated patients (73%; P=0.03). Only peak serum creatinine before biopsy and the use of immunosuppression influenced progression to ESRD. There was no significant difference in the 1-year mortality rates between these groups (46 vs 64%; P=0.3). However, when follow-up was extended beyond 2 years, immunosuppression was associated with a lower risk of death (HR 0.33, 95% CI 0.11-0.97) and death or ESRD (HR 0.16, 95% CI 0.06-0.42) in multivariable models.

Rituximab for the treatment of Churg-Strauss syndrome with renal involvement

Churg-Strauss syndrome (CSS) is a small vessel systemic vasculitis associated with asthma and eosinophilia that causes glomerulonephritis (GN) in ∼25% of patients. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that depletes B cells and is effective in numerous autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aim to evaluate the safety and efficacy of RTX in inducing remission of renal disease activity in patients with CSS. We conducted a single-center, open-label pilot study using RTX (375 mg/m(2)/week × 4) for induction of remission in CSS patients with renal involvement [defined as having >25% dysmorphic red cells, red blood cell casts or pauci-immune GN on biopsy]. Written informed consent was obtained from all individuals. Patients were eligible if they were untreated, had failed glucocorticoid therapy or had failed glucocorticoid dose reductions because of disease relapses. The primary outcome was remission of renal disease activity defined as stability or improvement of creatinine clearance, absence of active urinary sediment and reduction of the glucocorticoid dose to <50% of the average dose received over 3 months before enrollment or <10 mg/day (whichever is smaller) at 6 months. Patients were followed up for 1 year. Only three patients (two females; ages 54, 55 and 65) were enrolled. All patients had positive myeloperoxidase-ANCA and renal involvement. Two patients had biopsy-proven pauci-immune crescentic GN. All achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. One patient experienced a nonrenal relapse (eye and joint involvement) at 6 months coinciding with the reconstitution of CD19+ cells and eosinophilia. He was retreated with RTX and achieved remission within 6 weeks. No major adverse effects were recorded. In this pilot study, RTX was safe and successful in controlling renal disease activity in three patients with CSS. This agent deserves further study in CSS.

Expression of stem cell marker CD133 in fetal and adult human kidneys and pauci-immune crescentic glomerulonephritis.

Different cell types in the kidney, including those in tubules, glomeruli, and interstitium, have been proposed as candidate adult renal stem cells, raising controversy about the very existence of such cells. In this study, we sought to clarify the location and nature of adult renal stem cells and to address their reparative role in native kidney disease. The expression of the stem cell marker CD133 was analyzed in 31 normal fetal and adult human kidneys by immunohistochemical methods. Co expression of CD133 with Ki-67 and tubule specific markers was also examined. Seventeen cases of pauci-immune glomerulonephritis were evaluated for CD133 and Ki-67 expression, and this was correlated with the patients' renal prognosis. CD133 was expressed in S-shaped bodies of fetal kidneys and co-expressed with Ki-67. It was highly expressed in mature tubules of fetal and adult kidneys without Ki-67 co-expression. CD133+ cells were most abundant in the S3 segment of proximal tubules and co-expressed with the distal tubule marker, suggesting multipotency. Most tubular CD133+ cells in normal adult kidneys exhibited pathologic features of acute and chronic injury. In pauci-immune glomerulonephritis, tubular CD133 and Ki-67 co-expression tended to be higher in cases where renal function recovered. These results suggest that adult renal stem cells reside predominantly in the S3 segment of the proximal tubule, where they remain mitotically silent under normal conditions, but can be induced by cellular injury. These results also suggest a potential role for adult renal stem cells in recovery from native human kidney disease.

Coexistent Membranous Nephropathy with Doubly ANCA-Associated Crescentic Glomerulonephritis: A Case Report and Review of Literature

Introduction: Membranous nephropathy (MN) is the most common causes of the nephrotic syndrome in nondiabetic, Caucasian adults. Pauci-immune necrotizing and crescentic glomerulonephritis (PNCGN) typically present with rapidly progressive glomerulonephritis. Coexistent MN and PNCGN is a rare occurrence. We report a case of both MPO- and PR3-ANCA associated NCGN with MN that presented as rapidly progressive glomerulonephritis. Case presentation: A 46-year-old female presented with nausea and vomiting. On physical examination, the patient was a febrile and normotensive. Blood tests showed acute kidney injury and anemia. Urinalysis demonstrated numerous dysmorphic red blood cells with granular casts and nephrotic range proteinuria. Further testing showed negative ANA, positive anti-dsDNA, PR3-ANCA and MPO-ANCA. Kidney biopsy revealed the diagnosis of concurrent PNCGN with membranous nephropathy. The diagnosis of concurrent ANCA-associated NCGN with Membranous nephropathy was made. High dose intravenous methyl prednisolone was initiated. Unfortunately, the patient developed diffuse alveolar hemorrhage and underwent 6 cycles of plasmapheresis, intravenous Cyclophosphamide and pulse dose steroids with transitioned to oral prednisone and mycophenolate. On follow up, her disease seemed to be well suppressed without dialysis. Conclusion: Membranous nephropathy with PNCGN is a rare concurrent glomerulopathy, and even more rare with both MPO and PR-3 positivity. The diagnosis of MN with PNCGN should be considered in patients who present with RPGN and nephrotic range proteinuria.

Immune deposits in cutaneous lesions of Wegener's granulomatosis: predictor of an active disease.

A retrospective analysis was conducted of eight cases of Wegener's granulomatosis (WG), who presented with cutaneous lesions. The clinical, immunopathologic and histopathologic features of the cutaneous lesions were reviewed. Antineutrophil cytoplasmic antibody (ANCA) status of the patients was established. When possible, a comparison of immunofluorescence findings of skin biopsies was made with those of renal biopsies taken at the same time. In all except one, systemic and cutaneous disease developed concurrently. On histopathology, leukocytoclastic vasculitis was noted in five patients and features of lupus erythematosus and pyoderma gangrenosum in one case each. Four patients showed immunoglobulin deposits in subepidermal blood vessel walls, while one patient showed granular immune deposits at dermo-epidermal junction only. Immunoglobulin G was the most common immunoreactant detected. C-ANCA/proteinase 3 (PR3)-ANCA was positive in six patients, P-ANCA/myeloperoxidase (MPO)-ANCA in one patient, while one patient did not show ANCA positivity on indirect immunofluorescence. All four renal biopsies showed pauci-immune glomerulonephritis, irrespective of the presence (n=3) or absence (n=1) of immune deposits in the skin biopsy. Skin manifestations are encountered in nearly half of the patients with WG, thus it is important to be familiar with cutaneous histopathologic as well as immunofluorescence findings in WG patients.

Renal Neutrophils Infiltration in Antineutrophil Cytoplasmic Antibodies-Negative Pauci-Immune Crescentic Glomerulonephritis

IntroductionThis study aims to investigate the evidence of neutrophil infiltration in renal tissue from patients with antineutrophil cytoplasmic antibodies (ANCA)-negative pauci-immune crescentic glomerulonephritis (CrGN), and a comparison with their ANCA-positive counterparts was performed. MethodsRenal biopsy specimens from 31 patients with pauci-immune CrGN were collected. Twelve patients were ANCA negative, and 19 patients were ANCA positive. Neutrophil infiltration was investigated by staining of 2markers, CD15 and myeloperoxidase (MPO), using immunohistochemistry. ResultsPositive-stained cells of CD15 (CD15+) and MPO (MPO+) were mainly located in glomeruli with cellular crescents and segmental fibrinoid necrotic lesions and in periglomerular area of cellular crescents, especially at the area of ruptured Bowman capsule. Scanty positive staining was found in normal renal tissue. The number of CD15+ cells in the glomeruli and periglomerular area was significantly higher in ANCA-negative group than in ANCA-positive group (in glomeruli: 2.70 ± 1.61 versus 1.38 ± 0.85, P=0.019; in periglomerular area: 4.35 ± 4.36 versus 1.48 ± 1.67, P=0.047). The number of MPO+cells in the periglomerular area was also significantly higher in ANCA-negative group than that in ANCA-positive group. ConclusionsRenal neutrophil infiltration might play a pathogenic role in ANCA-negative pauci-immune CrGN, and the neutrophil infiltration might be more severe in ANCA-negative pauci-immune-CrGN than in ANCA-positive one.

A case of microscopic polyangiitis associated with aortic valve insufficiency

Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by inflammation of small-sized vessels. Although there have been some reports of ANCA-associated vasculitis presenting as aortitis syndrome, MPA rarely involves large-sized vessels such as the aorta. We report an unusual case of MPA combined with severe acute aortic valve insufficiency in a 56-year-old man. He initially presented with prolonged fever, skin rash, and rapidly progressive glomerulonephritis. P-ANCA and anti-myeloperoxidase (MPO) antibodies were positive, but the c-ANCA and anti-proteinase-3 antibodies were negative. Skin biopsy of the lower leg showed necrotizing arteritis. Kidney biopsy was also performed, which revealed diffuse necrotizing and crescentic glomerulonephritis (GN) consistent with pauci-immune ANCA-associated GN. Serial echocardiographic evaluations revealed aortic valve changes and worsening acute aortic valve insufficiency over a two-month period. Despite intensive treatment, our patient developed sudden cardiac arrest and died. Our patient demonstrated typical clinical features and histopathologic findings for systemic vasculitis and had a positive anti-MPO antibody, all of which were consistent with the diagnosis of MPA. Thus, MPA may have been the cause of acute aortic valve insufficiency in this case.

Rare Association of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, ANCAs, and Pauci-immune Crescentic Glomerulonephritis

We report a 69-year-old African American woman with hemoptysis and hematuria caused by a focally crescentic pauci-immune glomerular injury associated with the presence of antineutrophil cytoplasmic antibodies (ANCAs). An incidental diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma also was established based on the kidney biopsy. Given that a subset of patients with CLL can develop autoantibodies to red blood cells, platelets, or, rarely, neutrophils, the simultaneous presence of CLL, ANCA, and a pauci-immune crescentic glomerulonephritis may not be a coincidence. Recent advances in the pathogenic role of ANCAs in pauci-immune crescentic glomerulonephritis may link the underlying CLL to this patient's glomerular injury. Awareness of this possible association may be important for clinicians who manage patients with CLL, as well as for renal pathologists who diagnose pauci-immune crescentic glomerulonephritis.

Wegener's Granulomatosis Presenting With Colonic Ulcerations

A 79-year-old, otherwise healthy woman presented with a 3-day history of explosive diarrhea, abdominal cramping, and bright red blood per rectum. Rectal examination was notable only for trace bright red blood on the examining glove. Initial laboratory findings included hemoglobin of 10.0 g/dL and a total white blood cell count of 11.4 × 109/L. Stool studies were negative for Clostridium difficile and enteric pathogens. She underwent further evaluation with colonoscopy (Figure A), which revealed scattered ulcers ranging in size from 5 mm to 2 cm. In total, there were more than 20 ulcers scattered throughout the colon, except for cecal sparing. Ulcer borders were erythematous and edematous with white exudative bases, but without signs of active bleeding. The intervening mucosa between ulceration was normal. Cytomegalovirus immunostain was negative. Biopsies of the lesions showed foci of ulceration and hemorrhage within the lamina propria and scattered foci of cryptitis and crypt abscesses. Three days into her hospital course she developed new hypoxia and had apparently aspirated. A chest x-ray showed extensive infiltrates and consolidation in the left upper lobe, which was new compared with a film taken 10 days prior. She was treated for aspiration pneumonia. She was discharged to home with oxygen and instructions to complete a 10-day course of oral levofloxacin. She was readmitted 6 days later with worsened shortness of breath, intermittent hemoptysis, and acute renal failure (creatinine, 2.0 mg/dL). Unenhanced computed tomography of the chest showed extensive bilateral infiltrates in the upper lobes consistent with diffuse alveolar hemorrhage (Figure B). The patient was found to have a C-reactive protein of 253.9 mg/L and was positive for cytoplasmic anti-neutrophilic cytoplasmic antibody and equivocal for PR3. A renal biopsy demonstrated pauci-immune necrotizing and crescentic glomerulonephritis. A diagnosis of Wegener's granulomatosis (WG) was made. Our patient underwent treatment with cyclophosphamide and systemic steroids as well as plasma exchange for 14 days. Her respiratory status and renal function improved dramatically. She had no recurrence of gastrointestinal bleeding and was eventually discharged to home. Discrete colonic ulcerations can be seen in Crohn's disease, nonsteroidal anti-inflammatory drug ingestion, ischemia, or infectious processes (eg, amebiasis, Campylobacter or Yersinia infection.). However, in the context of new pulmonary infiltrates and renal failure, gastrointestinal involvement by vasculitis should be considered. WG, a disseminated, small-vessel necrotizing vasculitis, typically affects the kidneys and respiratory tract. In this rare case, WG initially presented with colonic ulcerations. Colonic ulcerations, typically presenting with lower gastrointestinal bleeding and diarrhea, are unusual manifestations of systemic vasculitides, but they have been described in WG.1Uribe A. Goobar J. Rubio C. et al.Colonic ulcerations in Wegener's granulomatosis.J Rheumatol. 1991; 18: 1429-1430PubMed Google Scholar, 2Wilson R.T. Dean P.J. Upshaw J.D. et al.Endoscopic appearance of Wegener's granulomatosis involving the colon.Gastrointest Endosc. 1987; 33: 338-339Abstract Full Text PDF Google Scholar At colonoscopy, multiple ulcerations with sharp borders, no surrounding inflammation, and in a nonspecific anatomic distribution are seen.1Uribe A. Goobar J. Rubio C. et al.Colonic ulcerations in Wegener's granulomatosis.J Rheumatol. 1991; 18: 1429-1430PubMed Google Scholar Characteristic histologic changes include the presence of granulomas and vasculitis; however, these are rarely reported in mucosal biopsy material.3Camilleri M. Pusey C.D. Chadwick V.S. et al.Gastrointestinal manifestations of systemic vasculitis.Q J Med. 1983; 52: 141-149PubMed Google Scholar In this case, biopsies of the colonic mucosa were largely nonspecific. This case illustrates that the differential for colonic ulcerations in patients with multisystemic disease should include vasculitis, specifically WG.

High-Mobility Group Box-1 Protein (HMGB1) Is Increased in Antineutrophilic Cytoplasmatic Antibody (ANCA)-Associated Vasculitis with Renal Manifestations

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is increasingly recognized as an important proinflammatory mediator actively secreted from monocytes and macrophages and passively released from necrotic cells. In antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), the kidneys are commonly affected vital organs, characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. The aim of the study was to determine whether HMGB1 serum levels are elevated in AAV with renal manifestations. A total of 30 AAV patients (16 female and 14 male; median age 59 years, range 17-82) with Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome with available renal biopsies and serum samples were included. In seven cases, serum was also obtained at rebiopsy in remission. HMGB1 was analyzed with Western blot. Birmingham Vasculitis Activity Score (BVAS, version 2003), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinanalysis, creatinine, estimated glomerular filtration rate, sex and age were included in the analysis. Twenty-five episodes of biopsy-proven active disease with BVAS 17.9 ± 4.6 and 13 cases with inactive biopsies and BVAS 2.3 ± 3.7 (P = 0.0001) were identified. CRP, ESR, hematuria and proteinuria were significantly higher in active cases. HMGB1 was significantly elevated (P = 0.01) comparing active with inactive cases (120 ± 48 versus 78 ± 46 ng/mL) and significantly lower in the seven control patients (P = 0.03) at rebiopsy in remission. HMGB1 remained higher in inactive cases compared with historic healthy controls (10.9 ± 10.5 ng/mL). HMGB1 levels did not differ significantly between AAV subgroups. CRP and ESR did not correlate with HMGB1. HMGB1 is significantly increased in AAV with renal involvement. Residual HMGB1 elevation in remission could possibly reflect low-grade inflammatory activity or tissue damage. Future studies may further reveal whether HMGB1 is useful as a marker of disease activity and a predictor of outcome in AAV.