Abstract
Hepatocyte growth factor and its receptor cMet activate biological pathways necessary for repair and regeneration following kidney injury. Here, we evaluated the clinical role of urinary cMet as a prognostic biomarker in diabetic nephropathy (DN). A total of 218 patients with DN were enrolled in this study. We examined the association of urine cMet levels and long-term outcomes in patients with DN. The levels of urinary cMet were higher in patients with decreased renal function than in patients with relatively preserved renal function (5.25 ± 9.62 ng/ml versus 1.86 ± 4.77 ng/ml, P = 0.001). A fully adjusted model revealed that a urinary cMet cutoff of 2.9 ng/mL was associated with a hazard ratio for end-stage renal disease of 2.33 (95% confidence interval 1.19–4.57, P = 0.014). The addition of urinary cMet to serum creatinine and proteinuria provided the highest net reclassification improvement. We found that in primary cultured human glomerular endothelial cells, TGFβ treatment induced fibrosis, and the protein expression levels of collagen I, collagen IV, fibronectin, and αSMA were decreased after administration of an agonistic cMet antibody. In conclusion, elevated levels of urinary cMet at the time of initial diagnosis could predict renal outcomes in patients with DN.
Highlights
Hepatocyte growth factor and its receptor cMet activate biological pathways necessary for repair and regeneration following kidney injury
Urinary soluble cMet levels as measured by enzyme-linked immunosorbent assay (ELISA) were significantly higher in patients with chronic kidney disease (CKD) stage V than in patients with CKD I, II, III, or IV (P < 0.001); this trend remained unchanged after urinary soluble cMet levels were adjusted for urinary creatinine (Fig. 1)
Elevated cMet values remained an independent variable associated with end-stage renal disease (ESRD) or the composite outcome after adjusting for confounding variables, including age, sex, hemoglobin, albumin, AST, ALT, uric acid, cholesterol, calcium, phosphorus, estimated glomerular filtration rate, and the urine protein-to-creatinine ratio (UPCR) (ESRD: hazard ratio (HR) 2.33, 95% confidence interval (CI) 1.19–4.57, P = 0.014; Composite outcome: HR 2.14, 95% CI 1.18–3.86, P = 0.012; Death: HR 1.88, 95% CI 0.81–4.39, P = 0.142)
Summary
Hepatocyte growth factor and its receptor cMet activate biological pathways necessary for repair and regeneration following kidney injury. Developing new ways to identify patients with a good prognosis from those with poor prognostic outcomes remains important for the management of individuals with diabetic nephropathy (DN). CMet, the tyrosine kinase receptor for HGF, has been shown to be critical for cell survival via stimulation of an array of downstream signaling pathways, resulting in cell proliferation, spreading, migration, and inhibition of apoptosis[8,13]. These pleiotropic events have generated profound interest regarding the potential therapeutic role of the HGF/Met pathway in animal models of kidney injury. Recent in vivo evidence supports a role for the HGF/Met pathway as an antifibrogenic factor because injection of recombinant HGF protein or the HGF gene led to reduced renal myofibroblast activation and diminished tubulointerstitial fibrosis[10,14,15]
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