Abstract
Gremlin renal overexpression has been reported in diabetic nephropathy, pauci-immune crescentic glomerulonephritis and chronic allograft nephropathy and has been implicated in the pathophysiology of the progression of renal damage. However, it is unknown whether urinary Gremlin can be associated with renal functional status, renal biopsy findings and outcome. To examine these associations we studied 20 patients with ANCA+ renal vasculitis and very high urinary Gremlin (354 ± 76 ug/gCr), 86 patients with other glomerular diseases and moderately elevated urinary Gremlin (83 ± 14 ug/gCr) and 11 healthy controls (urinary Gremlin 11.3 ± 2.4 ug/gCr). Urinary Gremlin was significantly correlated with renal expression of Gremlin (r = 0.64, p = 0.013) observed in cellular glomerular crescents, tubular epithelial cells and interstitial inflammatory cells. Moreover, urinary Gremlin levels were correlated with the number of glomerular crescents (r = 0.53; p < 0.001), renal CD68 positive cells (r = 0.71; p < 0.005), tubulointerstitial fibrosis (r = 0.50; p < 0.05), and serum creatinine levels (r = 0.60; p < 0.001). Interestingly, Gremlin expression was colocalized with CD68, CD163 (monocyte/macrophage markers) and CCL18 positive cells. ROC curve analysis showed that the cutoff value of urinary Gremlin in glomerular diseases as 43 ug/gCr with 72% of sensitivity and 100% of specificity [AUC: 0.96 (CI 95% 0.92–0.99] (p < 0.001). For ANCA+ renal vasculitis the value of urinary Gremlin of 241 ug/gCr had 55% of sensitivity and 100% of specificity [AUC: 0.81 (CI 95% 0.68–0.94) (p < 0.001]. Based on these results we propose that urinary Gremlin represents a non-invasive biomarker in ANCA+ renal vasculitis, and suggest a role of Gremlin in the formation of crescents.
Highlights
Gremlin belongs to a family of bone morphogenetic proteins (BMPs) antagonists[2,3,4] that have a well-recognized role in organogenesis and fibrotic related disorders[5,6,7] Gremlin is induced by TGF-β in renal cells[2], and it is a downstream mediator of TGF-β, activating the Smad pathway and inducing epithelial-mesenchymal transition[8]
Urinary Gremlin levels are elevated in pauci-immune crescentic glomerulonephritis
In order to define if these increased Gremlin values were only related to the presence of glomerular crescents, we compared the values in ANCA-crescentic glomerulonephritis with other glomerulopthies (IgA and Systemic Lupus Erythematosus (SLE) nephropathy) that presented crescents in more that 25% of the glomeruli
Summary
Gremlin belongs to a family of bone morphogenetic proteins (BMPs) antagonists[2,3,4] that have a well-recognized role in organogenesis and fibrotic related disorders[5,6,7] Gremlin is induced by TGF-β in renal cells[2], and it is a downstream mediator of TGF-β, activating the Smad pathway and inducing epithelial-mesenchymal transition[8]. Gremlin has been observed in various nephropathies, notably in pauci-immune crescentic vasculitis where strong expression of Gremlin mRNA and protein were observed at glomerular crescents, and in tubular and infiltrating interstitial cells[19]. It is not known if Gremlin is present in the urine during kidney injury and whether it could be a novel biomarker with diagnostic or prognostic value in glomerular diseases. C p >100 MPO p 20 MPO p 9 MPO p 93 MPO p 73 MPO p 10 MPO p nt p 84 MPO p 76 MPO p 18 MPO p nt p 9 MPO p 38 MPO c 7.4 PR3
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