NDT Advance Access originally published online on December 12, 2006
Nephrology Dialysis Transplantation 2007 22(5):1480-1481; doi:10.1093/ndt/gfl742
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New insight on crescentic glomerulonephritis
Email: hassan.izzedine{at}psl.aphp.frSir,
Diseases involving the renal glomeruli are encountered frequently in clinical practice and are the most common cause of end-stage renal disease worldwide. Crescentic glomerulonephritis and its clinical corollary, rapidly progressive glomerulonephritis (RPGN), is a potentially fatal disease and one of the few diagnostic emergencies that occur in nephrology in which affected individuals lose kidney function over a period of days to weeks. Early diagnosis is essential, as intervention can make a significant impact on minimizing irreversible kidney damage and improving patient outcomes.
The histopathological hallmark of RPGN is proliferation of cells in Bowman's space to form glomerular crescents, which may contain parietal epithelial cells, inflammatory cells and podocytes. Circulating factors [1,2] and chronic hypoxia [3] have been proposed as common pathogenic mechanisms of this disease.
The best classification of RPGN has divided patients into three groups on the basis of the underlying immunopathology: those with antibodies to glomerular basement membrane (GBM, e.g. Goodpasture syndrome), those with immune deposits and cellular proliferation within the glomerular tuft (e.g. infections, cryoglobulinaemic GN, etc.) and those without immune deposits (pauci-immune, e.g. Wegener's granulomatosis, microscopic polyangeitis, etc.) [4]. The incidence of pauci-immune RPGN is 1 out of 12 patients among those hospitalized for acute renal failure [5]. However, the pathogenesis of pauci-immune RPGN is incompletely understood and currently the role of the anti-neutrophil cytoplasmic antibodies (ANCA) in the pathogenesis and progression of this disease was recognized as a determinant of clinical management [1,2,6].
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 localized forms of these diseases (e.g. pauci-immune necrotizing and crescentic glomerulonephritis) [7].
However, 20% of individuals with pauci-immune RPGN never have circulating ANCA-specific antibodies and are diagnosed as ‘idiopathic’ pauci-immune GN [5]. Ding et al. [8] hypothesized an alternative pathogenic mechanism for negative-ANCA-pauci-immune RPGN. The authors suggested that podocytes are required for maintenance of glomerular capillary health and that an intrinsic defect within this cell population may trigger glomerular vasculitis and RPGN. They showed that the Von Hippel–Lindau gene (Vhlh) is required in the podocyte to maintain glomerular integrity. Loss of Vhlh leads to stabilization of hypoxia-inducible factor 
subunits (HIFs). From intrinsic glomerular cells of mice, loss of Vhlh initiates a necrotizing crescentic GN and the clinical features that accompany RPGN [8]. It has been identified de novo expression of the HIF target gene Cxcr4 [9] in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease [8].
The pathogenic mechanism identified by Ding et al. [8] may underlie 20% of pauci-immune RPGN that is ANCA-negative and provide a new clinical paradigm for the diagnosis of crescentic GN (Figure 1).
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Conflict of interest statement. None declared.
Department of Nephrology
Pitie-Salpetriere Hospital
Paris
France
References
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