Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy Frederick W.K. Tam a, * ,1 , Bruce L. Riser c,d,1 , Karim Meeran b , JoAnn Rambow c , Charles D. Pusey a , Andrew H. Frankel a a Imperial College Kidney and Transplant Institute, Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK b Endocrinology Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK c Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA d Renal Division, Baxter Healthcare, McGaw Park, IL, USA article info Article history: Received 18 September 2008 Received in revised form 2 March 2009 Accepted 1 April 2009 Keywords: Chemokine Diabetic nephropathy Growth factor MCP-1 Progression abstract Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6 years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p < 0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p < 0.01 and p < 0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R = 0.49, p < 0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R = 0.61, p < 0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or nor- moalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Diabetic nephropathy is a major cause of renal failure. Despite vigorous management, including treatment of hypertension, gly- caemic control and use of inhibitors of the renin angiotensin sys- tem (RAS), a significant proportion of diabetic patients develop chronic kidney disease and progress to end stage renal disease (ESRD). To optimise the use of current therapy, it would be of great benefit to identify not only diabetic patients who are likely to de- velop clinical nephropathy, but also those who will exhibit rapid progression despite appropriate treatment. There is increasing evidence that both chemokines and pro-fi- brotic growth factors are involved in the pathogenesis of diabetic nephropathy, acting by driving inflammatory and fibrotic pro- cesses. Transforming growth factor (TGF)-b has been demonstrated to have important role in the development of renal fibrosis in a variety of renal disorders, including diabetic nephropathy. While hyperglycaemia and intraglomerular hypertension are well estab- lished causal factors driving the progression of nephropathy in dia- betes, inflammation also contributes to pathogenesis, and may be involved both in its initiation and later stage disease. In support of this role for inflammation, increased number of macrophages have been reported in the renal biopsies of patients with diabetic nephropathy [1]. In experimental diabetic nephropathy, an in- creased number of glomerular macrophages was detected before gene expression and deposition of extracellular matrix compo- nents [2]. Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is a potent C–C chemokine for monocyte/macro- phages and T cells [3]. In the presence of high concentrations of glucose and advanced glycation end-products, cultured mesangial cells, podocytes and renal tubular epithelial cells have been shown to produce MCP-1 [4–6]. Recently, TGF-b has been shown to induce MCP-1 synthesis in a human proximal tubular cell line [7]. Further- more, increased amounts of MCP-1 are detected in the renal biop- sies and urine from patients with diabetic nephropathy [8–10]. Moreover, MCP-1 knockout mice have recently been shown to be protected from streptozotocin (STZ) induced diabetic nephropathy [11]. 1043-4666/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2009.04.001 * Corresponding author. Address: Imperial College Kidney and Transplant Insti- tute, Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Fax: +44 20 8383 2062. E-mail address: f.tam@imperial.ac.uk (F.W.K. Tam). 1 These authors are equally contributing co-senior authors. Cytokine 47 (2009) 37–42 Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666