Mechanisms of Diabetic Nephropathy

In patients with diabetic nephropathy, glomerulopathy is an important renal structural change

The kidney consists of four basic tissue types: vessels, glomeruli, tubules, and interstitium. Each of these types may be influenced by different pathophysiologic mechanisms associated with diabetic nephropathy. Despite their variability, these mechanisms share common clinical outcomes including microalbuminuria, progesssion to end-stage renal disease, and increased risks of cardiovascular morbidity and mortality.

Vascular mechanisms

Vascular mechanisms of diabetic nephropathy are related to the direct effects of increased BP on renal vascular tissues and the vascular consequences of altered hemodynamics, including endothelial dysfunction, calcification, and sclerosis. In patients with pathologic hemodynamics, low afferent arteriolar compared with elevated efferent arteriolar resistance exposes the glomerulus to an increased pressure load. This condition stimulates cytokine expression, resulting in al-terations in matrix material deposition that may contribute to inter-capillary glomerulosclerosis.

The glomerular filtration rate is increased in the early stages of diabetic nephropathy. The effects of diabetes on glomerular filtration stem, in part, from primary effects on the proximal tubule or loop of Henle that affect glomerular filtration via feedback through the macula densa (Am J Physiol. 2004;286:F8-F15). This mechanism helps explain the paradox of diabetic hyperfiltration in response to increased salt intake, as well as the renal response to dietary protein and amino acid infusion in animal models of diabetes.

The pathophysiologic mechanisms of diabetic hyperfiltration remain in-completely understood. In diabetic rats, single nephron hyperfiltration results from elevations in the glomerular capillary plasma flow rate and the glomerular capillary hy-draulic pressure, and these changes are associated with progressive albuminuria and morphologic injury (J Diabetes Complications. 1995;9:304-307). Selective control of glomerular capillary hypertension with ACE inhibitors limits glomerular injury in this model. Many studies invoke potential roles of endogenous vasoactive mediators in the pathogenesis of diabetic glomerulopathy, and recent evidence suggests that local renal tissue levels, rather than circulating levels, may play a greater role in hemodynamic regulation.

Glomerulopathy, characterized by mesangial expansion and thickening of the glomerular basement membrane, is the most important renal structural change in patients with diabetic nephropathy. Mesangial expansion is the hallmark of diabetic glomerulopathy and is closely related to the presence of hypertension and proteinuria. By restricting glomerular capillary filtration surface and luminal volume, mesangial expansion stimulates compensatory mechanisms designed to maintain glomerular filtration but which ultimately contribute to progressive renal damage (J Nephrol. 2001;14 Suppl 4:S51-S57).

Mesangial expansion is strongly related to renal functional parameters in patients with type 1 diabetes, but this structural-functional relationship is less precise in patients with type 2 diabetes. Serial renal biopsies performed five years apart in patients with type 1 diabetes and microalbuminuria reveal significant increases in mesangial fractional volume and mean glomerular volume without further interstitial expansion, and these changes correlate with increases in the albumin excretion rate (Diabetes Metab. 2000;26 Suppl 4:8-14). In patients with type 2 diabetes and microalbuminuria, glomerular lesions are milder than those found in similar patients with type 1 diabetes, and about 30% of these patients exhibit normal renal structure.

Glomerulopathy in patients with diabetic nephropathy is usually characterized by diffuse expansion of the mesangial matrix, a condition generally referred to as diffuse or intercapillary glomerulosclerosis. Less common is a nodular pattern of mesangial matrix expansion known as the Kimmelstiel-Wilson lesion. Most patients with type 2 diabetes and renal failure have evidence of glomerulosclerosis.

Glucose toxicity is a primary cause of glomerular injury in patients with diabetic nephropathy. Prolonged elevations in blood glucose levels result in the formation of glycation end products which interfere with normal collagen turnover and promote vessel permeability, matrix accumulation, and the formation of adhesion molecules. Angiotensin II increases efferent arteriolar pressure and plays a key role in autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and prolonged inappropriate increases in angio-tensin II lead to decreases in RBF and GFR and the release of cyto-kines and growth factors. An important glomerular consequence of these multiple cytokine activations is destruction of the podocytes, which (like neurons) are difficult to replace when lost (Diabetes. 2005;54:1626-1634).

Changes in the renal tubules are important for the development of progressive diabetic kidney disease. Tubular hypertrophy, reduced or-ganic ion transport, and other tubular changes usually develop before the onset of diabetic proteinuria. Furthermore, increased tubuloglo-merular feedback and defective uptake may independently contribute to hyperfiltration and urinary protein loss. In patients with diabetic nephropathy, renal function and prognosis correlate better with structural lesions in the tubules and cortical interstitium than with classical glomerular changes (Histo Histopathol. 2002;17:247-252).

Recent studies have focused on the possibility that albumin and other proteins that accumulate in the lumen of proximal tubular cells as a consequence of glomerular permeability dysfunction are a direct cause of tubular cell injury. Specific proteins that have been shown to be cytotoxic are transferrin/iron, lipoproteins and complement components, all of which appear in the urine in proteinuric states (Kidney Int Suppl. 1997;62:S29-S31). Lipids bound to albumin and lipoproteins, including oxidized low density lipoproteins, may induce oxidative stress on tubular cells and are potent cytotoxic molecules. Reabsorption of high molecular weight proteins may stimulate proximal tubular cells to produce matrix proteins, cytokines, chemoattractants and vasoactive mediators that may stimulate interstitial inflammation and scarring.

The overload of tubular cells with filtered proteins may play an important role in the progression of diabetic nephropathy by translating glo-merular protein leakage into cellular signals of interstitial inflammation. In models of progressive proteinuric nephropathy, albumin and IgG accumulation by proximal tubular cells is visualized early, prior to the interstitial infiltration of MHC-II-positive cells and macrophages (J Am Soc Nephrol. 1998;9:1213-1224). Osteopontin and other inflammatory mediators may be detectable in cells of proximal tubules congested with protein at sites of interstitial infiltration. These observations suggest that interstitial inflammatory reactions develop at the sites of protein overload, and that the proinflammatory response of tubular cells to protein challenge may be a key mechanism in the pathogenesis of diabetic nephropathy.

The interstitium functions as the "incubator" of many of the cy-tokines and other bioactive mediators of matrix accumulation and fibrosis that play important roles in the development and progression of diabetic nephropathy. Of these, the cytokine transforming growth factor-beta (TGF-beta) has emerged as an important factor in the development of renal hypertrophy and accumulation of extracellular ma-trix in patients with diabetes (Semin Nephrol. 2003;23:532-543). TGF-beta promotes renal cell hypertrophy and has powerful fibrogenic properties resulting from both stimu-lation of matrix synthesis and in- hibition of matrix degradation. In tissue cultures, high glucose concentrations increase TGF-beta expression and stimulate cellular hypertrophy and matrix production, and the hypertrophic and matrix-stimulatory effects of high glucose are prevented by anti-TGF-beta therapy. Several reports describe overexpression of TGF-beta or TGF-beta type II receptor in the glomerular and tubulointerstitial compartments in experimental diabetes mellitus. Myofibroblasts which over- produce extracellular matrix are present in the renal interstitium in patients with diabetes but are rarely seen in normal kidneys. The myofibroblasts appear to originate from interstitial fibroblasts transformed by TGF-beta.