Azurocidin-specific-ANCA-related idiopathic necrotizing crescentic glomerulonephritis

An 80-year-old woman who had rapidly progressive glomerulonephritis unaccompanied by systemic vasculitis is described. On renal biopsy, she showed necrotizing crescentic glomerulonephritis by light microscopy and pauci-immune glomerular lesions by immunofluorescent study. No dense deposits were present on electronmicroscopic study. On serum examination, indirect immunofluorescent study showed perinuclear pattern antineutrophil cytoplasmic antibody (ANCA), but myeloperoxidase-ANCA and proteinase 3-ANCA were both negative. Her serum reacted only to azurocidin excluding other ANCA antigens: bactericidal permeability-increasing protein, cathepsin G, elastase, lactoferrin, or lysozyme. Serum creatinine level decreased, and C-reactive protein turned negative after steroid therapy. Azurocidin-ANCA also turned negative. It is suggested that azurocidin-ANCA might have been related to the inflammatory process of pauci-immune necrotizing crescentic glomerulonephritis in this patient.     

Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis.

BACKGROUND: Among the cellular changes occurring in renal fibrosis, epithelial-mesenchymal cell transdifferentiation or transition (EMT) is a phenomenon characterized in epithelial cells by loss of epithelial markers and acquisition of mesenchymal phenotype and of fibrosing properties. METHODS: To test the hypothesis that EMT is involved in human pauci-immune crescentic glomerulonephritis (PICGN), we studied 17 renal biopsies from 11 PICGN patients for: (i) proliferating cell nuclear antigen (PCNA) and cell cycle inhibitors (cyclin-dependent kinase inhibitors) p27 and p57; (ii) cell lineage phenotype markers: podocalyxin, synaptopodin and GLEPP-1 for podocytes; CD68 for macrophagic epitope; CD3 for T lymphocytes; alpha-smooth muscle actin (alpha-SMA) for myofibroblasts; vimentin for mesenchymal cells; and cytokeratins (CKs) for parietal epithelial cells (PECs); (iii) glomerular fibrosis by labelling collagens I, III and IV, and heat-shock protein 47 (HSP47), a marker of collagen-synthesizing cells; and (iv) co-localization of alpha-SMA, CK and HSP47 using confocal laser microscopy. RESULTS: The crescent cells proliferated greatly. They did not express p27 and p57. Different cell lineage markers could be identified in crescents: the major component was made of 'dysregulated' PECs negative for CK, followed by PECs positive for CK, macrophagic cells and myofibroblasts. Furthermore, some cells co-expressed CK and alpha-SMA. This latter co-expression suggests a transitional phase in the dynamic phenomenon of EMT. Therefore, proliferative and dysregulated glomerular epithelial cells could be a possible cellular source of myofibroblasts via EMT. In addition, HSP47 labelled many crescent cells and frequently co-localized in CK-positive epithelial cells and in alpha-SMA-positive myofibroblasts, indicating that these cells were involved in glomerular accumulation of collagens. CONCLUSION: EMT is a transient cellular phenomenon present in glomeruli in human PICGN contributing to the formation of myofibroblasts from epithelial cells and to glomerular fibrosis.     

The increase of antiglomerular basement membrane antibody following pauci-immune-type crescentic glomerulonephritis

A 50-year-old woman was admitted because of high fever and fatigue. Proteinuria, hematuria, and elevated BUN (47.8mg/dl) and creatinine (3.4mg/dl) suggested rapidly progressive glomerulonephritis. The serological study revealed all negative results for rheumatoid factor, antinuclear antibody, serum cryoglobulins, MPO-ANCA, PR3-ANCA, and anti-streptolysin O. Antiglomerular basement membrane (GBM) antibody, as assessed by ELISA, was 11EU (normal, <10). Kidney biopsy on the eighth hospital day demonstrated pauci-immune-type crescentic glomerulonephritis without ANCA. Methylprednisolone pulse therapy (500mg/day, 3 days) and 45mg/day prednisolone orally were started. At 3 weeks after kidney biopsy, the anti-GBM antibody value increased from 11EU/ml to 116EU/ml, and MPO and PR3-ANCA were still negative. HLA type was DR8 and DR 15(2), with a genotype of HLA-DRB1*08021 and HLA-DRB1*15011. The present case suggests that HLA-DR15 plays an important role on antibody production against alpha 3(IV) NC1 autoantigen after severe nephritis or tissue damage.     

Preexisting crescentic glomerulonephritis in the renal allograft

Two patients who received cadaveric renal transplants from the same donor were found to have similar diffuse proliferative glomerular lesions on renal biopsies performed for delayed graft function. The donor had no known disease, but had subtle abnormalities on preprocurement urinalysis. In retrospect, lupus nephritis is suspected in the donor. The authors detail the course of these 2 patients, review the literature on preexisting glomerular lesions, and address issues with regard to donor selection.     

The role of flow cytometric ANCA detection in screening for acute pauci-immune crescentic glomerulonephritis.

BACKGROUND: Most cases of pauci-immune crescentic glomerulonephritis (PICGN) are associated with serum anti-neutrophil cytoplasmic antibodies (ANCA). This article studied the sensitivity and specificity of serum ANCA, determined by flow cytometry and indirect immunofluorescence (IIF), to identify patients with acute PICGN. METHODS: 577 adults presenting for first biopsy of their native kidneys with serum taken for ANCA (flow cytometry and IIF) determination were studied. A positive ANCA was defined using a flow cytometric ANCA assay as a screening test, followed by a slide-based indirect IIF technique. Pathological confirmation of acute PICGN was used to assess the sensitivity and specificity of this combined approach and its positive predictive value (PPV) and negative predictive value (NPV) in patients presenting for renal biopsy due to abnormal urinary sediment. RESULTS: Forty-nine patients were found to have acute PICGN on renal biopsy. Of these 47 were ANCA positive (sensitivity 95.9%). Overall 93 of the renal biopsy patients were ANCA positive, (specificity 91.3%). A further seven patients (two ANCA positive) had advanced sclerosing disease consistent with PICGN but without evidence of current disease activity. The PPV and NPV of ANCA, assessed by flow cytometry and slide IIF, in predicting that patients presenting with undifferentiated renal disease would have acute PICGN was 50.5 and 99.8%, respectively. CONCLUSIONS: Flow cytometric screening of serum for ANCA in patients undergoing renal biopsy has a high NPV for determining those with acute PICGN. It may provide a rapid, simple screening test for this lesion in laboratories using diagnostic flow cytometry and may complement IIF/ELISA in evaluating ANCA positive patients.     

Impact of clinical and histopathological factors on outcome of egyptian patients with crescentic glomerulonephritis

This study included 128 patients with crescentic glomerulonephritis (CGN) having sufficient clinical and histopathological data and were followed up in our institute for a mean period of 34 +/- 28 months. There were 49 males and 79 females with mean age 22.7 +/- 14 years. We studied the effect of clinical, laboratory and histopathological parameters on kidney function and patient survival at the end point of the study. The multivariate analysis revealed that serum creatinine at presentation, nephrotic range proteinuria during the follow up period, percentage of glomeruli affected by crescents, percentage of fibrous crescents and absence of cellular infiltration were significant risk factors affecting the kidney function at termination of the study. The only risk factor which correlated significantly with the patient mortality was the serum creatinine at last follows up.     

Antineutrophil cytoplasmic antibody-negative pauci-immune crescentic glomerulonephritis associated with rheumatoid arthritis: An unusual case report

Clinically relevant renal lesions in rheumatoid arthritis (RA) are not common. More often renal involvement is related to complications of therapy than the disease itself. The most common forms of primary renal disease in RA are membranous glomerulonephropathy and a pure mesangial proliferative glomerulonephritis. Some studies have described the association between crescentic glomerulonephritis (crescentic GN) and RA, but they were all found to be perinuclear antineutrophil cytoplasmic antibody (p-ANCA) positive. However, RA associated with ANCA negative pauci-immue crescentic GN has not been reported. This is a case report of a 37-year-old female with RA who initially presented with general oedema and acute deterioration of renal function. The renal biopsy revealed ANCA negative pauci-immune crescentic GN. The patient was treated with steroid pulse and plasmapheresis, but not cyclophosphamide because of severe urosepsis. Despite the use of aggressive therapy, her renal function was not improved and she underwent maintenance haemodialysis thereafter. Because ANCA negative crescentic GN may occur in RA patients without frank systemic vasculitis, but with severe clinical manifestation, a heightened suspicion for a relatively 'silent' crescentic GN would have led to the correct diagnosis and appropriate treatment.     

Hepatocyte growth factor and its receptor Met are induced in crescentic glomerulonephritis.

BACKGROUND: In experimental extracapillary glomerulonephritis (EG) podocytes migrate, proliferate and change phenotype, and play a pivotal role in crescent formation. Hepatocyte Growth Factor (HGF) is an injury-induced effector of tissue repair that causes cell migration, growth and transdifferentiation via its receptor Met. METHODS: In 11 patients with EG we measured serum levels of HGF and investigated whether serum induces the release of HGF by Peripheral Blood Mononuclear Cells (PBMC). In renal biopsies we studied the expression of Met. In cultured podocytes we studied Met expression, migration, growth and morphological changes induced by recombinant (r) HGF. RESULTS: In patients with EG average serum levels of HGF (0.73 ng/ml) were higher than in normal volunteers (N, 0.10 ng/ml, p<0.01) and in patients with non-crescentic glomerular disease (GD, 0.18 ng/ml, p<0.01). Serum of EG induced a significant HGF release by PBMC (mean 0.58 ng/ml) in comparison with serum of N and GD (0.07 and 0.06 ng/ml, respectively, both p<0.001). Met was strongly expressed in crescents. Cultured podocytes expressed Met, and rHGF induced in podocytes a time- and dose-dependent migration, growth and epithelial to mesenchymal transdifferentiation. CONCLUSIONS: These results suggest that HGF/Met system participates in the process of crescent formation by inducing podocyte migration, growth and mesenchymal transformation.     

Hemorrhagic complications associated with PR3-ANCA crescentic glomerulonephritis

Abstract

Hemorrhagic complications of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis are life-threatening conditions. Of these, alveolar hemorrhage is the most common and well-described hemorrhagic complication and is a prominent component of the pulmonary-renal syndrome. The clinical presentation of alveolar hemorrhage is highly variable ranging from mild to serious disease that may require respiratory support. Less attention has been directed at hemorrhagic complications that have been reported in other organs and which may be as severe or more severe with regard to morbidity and mortality. For example, among the most serious non-pulmonary complications are those related to cerebral and gastrointestinal hemorrhage. Cerebral hemorrhage is the clearly the most critical issue with a persistent high mortality rate. The prognosis of gastrointestinal hemorrhage, once an ominous complication has improved with medical and surgical intervention. Not to be dismissed are the consequences of hemorrhagic issues related to skin, soft tissue or muscle involvement. Muscle hematomas, while rare, also accompanied by significant morbidity.     

Anti-endothelial cell antibodies in antineutrophil cytoplasmic antibodies negative pauci-immune crescentic glomerulonephritis

Aim: Pauci‐immune crescentic glomerulonephritis (CrGN) is frequently associated with circulating anti‐neutrophil cytoplasmic antibodies (ANCA). However, in patients with ANCA‐negative pauci‐immune CrGN, the pathogenesis is not clear. Anti‐endothelial cell antibodies (AECA) have been implicated in the pathogenesis of vasculitis. The purpose of this study is to investigate the prevalence of AECA and their possible clinical significance in ANCA‐negative pauci‐immune CrGN. Methods: Sera from 19 patients with ANCA‐negative pauci‐immune CrGN, 26 patients with ANCA‐positive pauci‐immune CrGN and 10 healthy blood donors were collected. Soluble proteins extracted from cultured human umbilical vein endothelial cells were used as antigens and western blot analysis was carried out to detect AECA. Results: In ANCA‐negative pauci‐immune CrGN, 10 of 19 patients were serum IgG‐AECA positive and seven bands reactive with endothelial antigens could be blotted. The prevalence of skin rash and thrombocytosis was significantly higher in patients with anti‐76 kDa and anti‐123 kDa autoantibodies than in patients without, respectively. Birmingham Vasculitis Activity Scores of patients with anti‐200 kDa AECA were significantly higher than in patients without. In the sera of 26 ANCA‐positive cases, 23 were AECA positive and 11 bands could be recognized. The prevalence of total AECA and anti‐90 kDa AECA was significantly lower in patients with ANCA‐negative pauci‐immune CrGN than in patients with ANCA‐positive pauci‐immune CrGN. Conclusion: Anti‐endothelial cell antibodies could be found in sera of patients with ANCA‐negative pauci‐immune CrGN; some AECA might have some clinical significance. The discrepancies of AECA might be a possible contributor to the differences between ANCA‐negative and ANCA‐positive pauci‐immune CrGN.     

The clinical and pathological characteristics of Chinese patients with pauci‐immune crescentic glomerulonephritis

SUMMARY In the present study, we investigated pauci‐immune crescentic glomerulonephritis (PICGN) in Chinese patients. During 13 years (1985–98), 6400 patients underwent non‐transplanting renal biopsy in the Nanjing Jinling Hospital. Twenty‐four patients were diagnosed as having PICGN. They were 16 women and eight men with a median age of 33 (range 10–76 years). Microscopic polyarteritis (33.3%) and polyarteritis nodosa (8.3%) were the secondary diseases. The incidence of PICGN was 0.37% in renal biopsies and 22.9% in crescentic glomerulonephritis. Clinically, most patients (75.0%) showed rapidly progressive nephritis with enlarged kidneys. Onset gross haematuria was noted in 58.3% of the patients, hypertension 45.8%, nephrotic syndrome 41.7%, and oliguria 25.0%. However, systemic symptoms were rare except anaemia. Pathologically, we observed necrosis of glomerular capillaries (62.5%), infiltration of monocytes and neutrophil cells in glomeruli (66.7%), and vasculitis in interstitium (53.3%), in addition to glomerulosclerosis more than 50% (45.8%), severe tubular atrophy (83.3%) and interstitial fibrosis (75.0%). Antineutrophil cytoplasmic antibodies were positive in 52.2%. All patients except two received intensively immunosuppressive therapy. Sixteen patients were subjected to long‐term follow up (median 29.8, range 8–92 months), 12 of them had life‐sustaining renal function, four had normal range of serum creatinine (< 124 μmol/L), only four patients were dialysis dependent.     

Drug-induced MPO-ANCA-positive necrotizing crescentic glomerulonephritis preceded by granulomatous hepatitis

A 67-year-old man being treated with allopurinol, furosemide, digoxin, and tamocapril for congestive heart failure and paroxysmal atrial fibrillation was admitted to our hospital because of intermittent fever, general fatigue, and liver dysfunction. On admission, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, and the titer was high. Discontinuation of all four drugs led to improvement of the symptoms, but the patient's renal function deteriorated. Liver biopsy showed granulomatous hepatitis (GH), and renal biopsy findings led to a diagnosis of pauci-immune necrotizing crescentic glomerulonephritis (CGN). The patient's renal function spontaneously improved without immunosuppressive therapy, and the MPO-ANCA titer decreased. We speculate that some common pathway induced by the drugs, possibly allopurinol, led to the two different clinical diseases, GH and CGN. Received: December 21, 2001 / Accepted: March 25, 2002     

Report on intensive treatment of extracapillary glomerulonephritis with focus on crescentic IgA nephropathy

PURPOSE AND DESIGN OF STUDY.: In this retrospective analysis the effects of combined treatmentwith steroid pulses, cyclophosphamide and plasma exchange onsix crescentic IgA glomerulonephritis (IgAGN) patients, selectedon a histological basis, were examined. The histological criteriaincluded involvement of more than 40% of glomeruli by cellularcrescents. The effects of this treatment were compared to thoseobserved in three untreated crescentic IgAGN patients and 12treated patients who had extracapillary glomerulonephritis ofdifferent origins, i.e. ANCA-associated systemic or renal-limitedvasculitis. All patients, except the three crescentic untreatedIgAGN patients, received the same 2-month treatment accordingto a standardized protocol: steroid boli 15 mg/kg methylprednisolonefor 3 consecutive days by intravenous infusion, followed byprednisone per os (1 mg/kg/day for 4 weeks, 0.75 mg/kg/day for4 more weeks), cyclophosphamide per os 2.5 mg/kg/day for 8 weeks,and plasma exchange. RESULTS.: After this 2-month course of therapy, substantial clinical improvementwas observed in both IgAGN and vasculitis patients. However,a second biopsy revealed that florid crescents persisted inIgAGN patients and, unlike the vasculitis group, during thelong-term the initial clinical amelioration disappeared in one-halfof the treated IgAGN cases. Nevertheless, even in the progressivecases, intensive treatment seemed to substantially delay theonset of dialysis. CONCLUSIONS.: Despite some clinical benefits of therapy, short-term reversalof active crescents appears less likely to occur in crescenticIgAGN than in vasculitis-associated crescentic GN. Intensivetreatment seems sufficient to arrest, but inadequate to reverse,phlogistic lesions in IgAGN before development of chronic changes.     

First report of tropical myositis and crescentic glomerulonephritis in a renal transplant recipient

We describe a renal transplant recipient who presented with tropical myositis and acute allograft dysfunction 2½ years after transplantation. Graft biopsy showed immune-complex crescentic glomerulonephritis. He was receiving only 7.5 mg/d of prednisolone for more than 2 months before presentation. Renal function did not improve despite treatment with antibiotics, methylprednisolone pulse therapy, and cyclophosphamide. He died of septicemia.     

Pauci-immune rapidly progressive glomerulonephritis after nephrectomy in a renal donor

Idiopathic rapidly progressive glomerulonephritis (RPGN) is a clinicopathologic syndrome in which glomerular damage is accompanied by a rapid and progressive decline in renal function, usually resulting in irreversible renal failure in weeks or months. We report the occurrence of pauci-immune RPGN, more specifically microscopic polyarteritis nodosa (PAN), in a 60-year-old woman 15 months after donor nephrectomy, and 3 months after documentation of intact, residual renal function. The transplanted kidney continues to function well in the recipient, 6 years posttransplantation, and 4.5 years beyond destruction of the donor's contralateral kidney by RPGN. The donor underwent cadaveric renal transplantation after 2 years on dialysis, and at the 3-year mark has intact renal function. These intriguing observations strongly argue that host environmental factors, rather than intrarenal factors, play a major causative role in the pathogenesis of RPGN.