Diabetic nephropathy is responsible for 30%-40% of all CKD cases and approximately 45% of end-stage renal disease (ESRD) cases in the United States.
In 2006, the U.S. Renal Data System recorded a prevalence of 506,256 individuals with ESRD and program Medicare expenditures of $33.5 billion (Am J Kidney Dis. 2009;53:S8-S374, vi-vii). These numbers are consistent with the 2001 predicted prevalence of 650,000 ESRD cases and $28 billion Medicare expenditures for the year 2010.
In 2005, it was predicted that the prevalence of ESRD will be as high as 712,290 by the year 2015. Given the accuracy of previous predictions, it is of great concern that we may indeed attain or possibly surpass the 2005 predictions for the year 2015, particularly as the incidence of diabetes continues to rise.
In terms of CKD stages 1-4, Coresh et al reported an increase in prevalence from 10% to 13.1% between the periods 1988-1994 and 1999-2004 (JAMA, 2007;293:2038-2047).
Unfortunately, the current economic environment and condition of our health-care system indicate that our resources will be unable to meet the growing needs of this population. Early identification of diabetic nephropathy via the use of meaningful biomarkers and prompt intervention to delay CKD progression are therefore crucial measures to prevent the continuing rise in CKD prevalence.
Albuminuria has long been a proven biomarker of injured kidneys and is an important predictor of poor renal and cardiovascular outcomes.
However, albuminuria, or more specifically microalbuminuria (30-300 mg of urinary albumin in 24 hr), is more consistently a predictor of endothelial dysfunction and cardiovascular disease risk than a reliable sign of enduring renal damage, whereas macroalbuminuria and overt proteinuria (greater than 300 mg of urinary albumin in 24 hr) represent established kidney damage and thus are more reliable predictors of poor renal prognosis.
Indeed, albuminuria may not be the ideal biomarker of diabetic nephropathy. In particular, for some patients with type 1 and type 2 diabetes, the presence of microalbuminuria heralds the existence of already established glomerular lesions while in other patients, microalbuminuria does not necessarily indicate progression to ESRD (J Am Soc Nephrol. 2006;17:339-352 and Diabetes Res Clin Pract. 2009;83:1-8).
Nonetheless, albuminuria remains the best currently available predictor for progression of diabetic nephropathy. While screening for albuminuria as an indicator for diabetic nephropathy is routinely performed for patients with known diabetes, there are case reports in which patients with biopsy proven diabetic nephropathy do not demonstrate clinical evidence of diabetes until much later in their course. The diagnosis of diabetic nephropathy based on clinical evidence of hyperglycemia and albuminuria alone is therefore inadequate.
As we learn more about the natural course and structural and signaling mechanisms of diabetic nephropathy (Vasc Health Risk Manag. 2008;4:575-596 and Cell Mol Biol (Noisy-le-grand). 2003;49:1319-1325), we recognize that glomerulosclerosis due to accumulation of mesangial matrix, interstitial fibrosis, and podocyte injury are integral parts of the pathogenic mechanisms.
This paper focuses on our current understanding of the role of fibrosis and on potential novel biomarkers. Identification of these biomarkers may facilitate establishment of new therapeutic targets for altering the progression of diabetic nephropathy. The hope is that recognition of more useful biomarkers may better correlate with disease commencement, progression, and outcome.
Cell adhesion molecules
The accumulation of extracellular matrix (ECM) components and the development of fibrosis are fundamental processes that occur in response to chronic hyperglycemia, intraglomerular and systemic hypertension, dyslipidemia, and oxidative stress.
These processes initiate expression of growth factors, cytokines, mediators, and modulators that perpetuate the overproduction of matrix proteins and families of cell adhesion molecules (CAMs). CAM families include intercellular adhesion molecules (ICAMs) and vascular adhesion molecules (VCAMs) produced by endothelial cells; integrins produced by mesangial, endothelial, and epithelial cells; and osteopontin and some laminins, which are matrix glycoproteins.
Under normal physiologic conditions, these components provide the structural support and communication necessary between resident cells and their environment for homeostasis, but under the chronic influence of the diabetic milieu, their altered expression becomes pathologic. Targeted remodeling of the ECM is currently thought to be an important therapeutic strategy to both delay the progression and induce regression of established lesions of CKD.
The renin-angiotensin-aldosterone system (RAAS) plays an important contributory role in this remodeling (Am J Nephrol. 2004;24:549-556), because blockade of components of the RAAS with the use of an ACE inhibitor, type I angiotensin receptor blocker (ARB), or a direct renin inhibitor (DRI) have proven utility in delaying disease progression (Vasc Health Risk Manag. 2009;5:411-427).
Accumulation of glomerular ECM components has two underlying causes. The first is an imbalance of cytokines (transforming growth factor-b; TGF-b) and growth factors, including insulin-like growth factor (IGF), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor-b (PDGF), fibroblastic growth factor (FGF), epithelial growth factor (EGF) and bone morphogenetic proteins (BMPs), especially BMP-7.
The other cause of ECM accumulation is an altered protease system consisting of matrix metalloproteinases (MMPs) and plasminogen activator inhibitor-1 (PAI-1) which are expressed by mesangial and endothelial cells and podocytes (See Figure 1). In several studies, these mediators have been shown to directly influence the turnover of ECM proteins in the development of diabetic nephropathy; their expression may be altered with blockade of the RAAS.
In particular, CAMs are important participants in mediating interactions between renal cells, the basement membrane, and matrix proteins and also play an important role in renal morphogenesis, renal health, nephropathy, and tissue repair. Strong research efforts over the years have indicated that the expression of a number of CAMS can be identified in the circulation, urine, or both and correlate with disease progression and appropriate treatment of diabetic nephropathy.