Search

Purpose of review Crescents are classical histopathological lesions found in severe forms of rapidly progressive glomerulonephritis, also referred to as crescentic glomerulonephritis (CGN). Crescent formation is a consequence of diverse upstream pathomechanisms and unraveling these mechanisms is of great interest for improving the management of patients affected by CGN. Thus, in this review, we provide an update on the latest insight into the understanding on how crescents develop and how they resolve. Recent findings Cellular crescents develop from activated parietal epithelial cells (PECs) residing along Bowman's capsule and their formation has as a consequence the decline in glomerular filtration rate (GFR). Cellular crescents can be reversible, but when multilevel growth of PECs associate with an epithelial--mesenchymal transition-like change in cell phenotype, fibrous crescents form, and crescents become irreversible also in terms of GFR recovery. Different molecular pathways trigger the activation of PECs and are a prime therapeutics target in CGN. First, crescent formation requires also vascular injury causing ruptures in the glomerular basement membrane that trigger plasmatic coagulation within Bowman's space. This vascular necrosis can be triggered by different upstream mechanisms, such as small vessel vasculitides, immune complex glomerulonephritis, anti-GBM disease, and C3 glomerulonephritis, that all share complement activation but involve diverse upstream immune mechanisms outside the kidney accessible for therapeutic intervention. Summary Knowing the upstream mechanisms that triggered crescent formation provides a tool for the development of therapeutic interventions for CGN.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium&rsquo, s Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1&ndash, 21). The percentage of crescents was 3&ndash, 100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1&ndash, 11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival (p = 0.003) and a 2% decrease in log odds of renal survival at last follow-up (p &lt, 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.

MIP-1α and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Background The precise molecular mechanisms of macrophage (Mϕ) recruitment and activation in crescentic glomerulonephritis remain to be investigated. We hypothesized that locally produced macrophage inflammatory protein (MIP)-1α and monocyte chemoattractant protein (MCP)-1 via the chemokine receptors participate in the pathophysiology of human crescentic glomerulonephritis by recruiting and activating Mϕ. Methods We investigated the levels of MIP-1α and MCP-1 by enzyme-linked immunosorbent assay (ELISA) in 20 healthy subjects, 20 patients with crescentic glomerulonephritis, and 41 control patients with various other renal diseases. The presence of MIP-1α, MCP-1, and the cognate chemokine receptor for MIP-1α, CCR5, in the diseased kidneys was evaluated by immunohistochemical and in situ hybridization analyses. Results MIP-1α–positive cells were mainly detected in crescentic lesions, whereas MCP-1 was mainly in the interstitium. In addition, we detected CCR5-positive cells in diseased glomeruli and interstitium. Urinary MIP-1α was detected in crescentic glomerulonephritis, even though it was below detectable levels in healthy subjects and in patients with other renal diseases without crescents. Urinary MIP-1α levels in the patients with crescentic glomerulonephritis were well correlated with the percentage of cellular crescents and the number of CD68-positive infiltrating cells and CCR5-positive cells in the glomeruli. However, urinary MCP-1 levels were well correlated with the percentage of both total crescents and fibrocellular/fibrous crescents and the number of CD68-positive infiltrating cells in the interstitium. Moreover, elevated urinary levels of both MIP-1α and MCP-1 dramatically decreased during glucocorticoid therapy-induced convalescence. Conclusions These observations suggest that locally produced MIP-1α may be involved in the development of cellular crescents in the acute phase via CCR5 and that MCP-1 may be involved mainly in the development of interstitial lesions in the chronic phase when fibrocellular/fibrous crescents are present, possibly through Mϕ recruitment and activation.

Detection of urinary macrophages expressing the CD16 (FcγRIII) molecule: A novel marker of acute inflammatory glomerular injury. Background The CD16 antigen is the Fcγ receptor III. CD14+CD16+ cells are proinflammatory monocytes/macrophages (Mo/MΦ) that constitute a minor population in the peripheral blood of healthy individuals. Little is known about the expression of CD16 antigen on Mo/MΦ in glomerulonephritis. Methods Flow cytometric analyses were performed on urine and blood samples obtained from 209 patients with various renal diseases. Patients variously suffered from rapidly progressive crescentic glomerulonephritis (RPGN), membranoproliferative glomerulonephritis (MPGN), postinfectious acute glomerulonephritis (AGN), Henoch-Schonlein purpura nephritis (HSPN), IgA nephropathy (IgAN), membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), lupus nephritis (LN), acute interstitial nephritis, hereditary nephropathy, idiopathic renal hematuria (IRH), and renal stone. Results The CD16+ MΦ population of cells was present in the urine of hematuria-positive patients with proliferative glomerulonephritis, including AGN, IgAN, RPGN, MPGN, and LN with acute inflammatory lesions, such as endocapillary proliferation, tuft necrosis, and cellular crescents. In contrast, the urinary CD16+ MΦ population was negligible in hematuria-positive patients with nonproliferative renal disease, including hereditary nephropathy, IRH, and renal stone and also in patients with proliferative glomerulonephritis lacking acute inflammatory lesions. Total urinary MΦ of these patients were much less than those of patients having proliferative glomerulonephritis with acute inflammatory lesions. Transient expansion of the CD16+ MΦ population in urine was observed during the acute exacerbation of urinary abnormalities, whereas the disappearance of CD16+ MΦ closely preceded the amelioration of urinary abnormalities in patients with proliferative glomerulonephritis. In 38 of the 98 patients positive for CD16+ MΦ population in urine, the CD16+ Mo population was negligible in peripheral blood. Immunohistochemically, CD16+ MΦ were present in the glomeruli of active proliferative glomerulonephritis, whereas such cells were absent in inactive proliferative glomerulonephritis or nonproliferative glomerular diseases. Conclusion CD16+ MΦ may be effector cells involved in the acute inflammation common to all types of proliferative glomerulonephritis. Furthermore, the detection of CD16+ MΦ in urine, as well as urinary MΦ counts, may serve as a useful indicator of the active stage of proliferative glomerulonephritis.

A new morphologic index for the evaluation of renal biopsies in lupus nephritis. Background Various morphologic indices for the evaluation of renal biopsies in lupus nephritis have been developed, of which the most successful have been the NIH Activity Index (AI) and Chronicity Index (CI). We wished to develop a biopsy index from standard light and immunofluorescence (IF) material that would correlate yet more closely with clinical and outcome parameters than the current indices, and be applicable to both treated and untreated cases. Methods A cohort of 71 patients with lupus nephritis who had initial renal biopsies (Bx1) with systematic second biopsies (Bx2) at six months after induction therapy was studied, with a large number of light microscopic and IF variables evaluated. These were examined statistically to choose the combinations of variables with the highest overall correlations with clinical and outcome parameters. Results The adopted biopsy index comprised four elements: Glomerular Activity Index (GAI), a modification of the standard AI with the addition of glomerular monocytes and elimination of interstitial inflammation; Tubulointerstitial Activity Index (TIAI), evaluating several tubular epithelial and inflammatory components, including interstitial inflammation, but excluding tubular atrophy; Chronic Lesions Index, a modification of the standard CI, with the addition of glomerular scars; IF Index (IFI), a semiquantitative index of IF staining for six standard antisera for glomerular capillary, mesangial, tubulointerstitial, and vascular elements. The Biopsy Index showed a statistically higher correlation with clinical and outcome parameters than the NIH AI ( P = 0.0170), the NIH CI ( P = 0.0009), or their combination ( P = 0.0444). At Bx1, comparisons between correlation coefficients for the appropriate AI or CI value and for the Biopsy Index, were: anti-DNA antibodies (0.30 vs. 045), serum creatinine (S Cr ; 0.33 vs. 0.48), proteinuria (0.22 vs. 0.36), hemoglobin (-0.21 vs. -0.45), and final renal function (0.22 vs. 0.40). Spearman rank correlations showed similar superiority for outcome parameters: doubling of S Cr (0.1810 vs. 0.3018) and end-stage renal disease (0.0529 vs. 0.1925). The same improvement of correlations was seen at Bx2 for most parameters, particularly doubling of S Cr (0.2716 vs. 0.4753). Conclusions The Biopsy Index and/or its components show better correlations with clinical and outcome parameters than the standard AI and CI and other similar indices.