Advocating for Patients with Diabetic Nephropathy

Although no cure exists, pharmacologic and nonpharmacologic measures can help patients prevent onset or progression of diabetic nephropathy to preserve kidney function.

Diabetes is the seventh-leading cause of death in the United States and the primary cause of end-stage renal disease. Diabetic nephropathy is a longterm consequence of diabetes, estimated to affect 20% to 40% of patients with diabetes. Although there is no cure for diabetic nephropathy, by understanding the pathophysiology, preventative strategies, and interventions to slow the progression of this disease, the pharmacist can be better prepared to advocate for kidney function preservation.

Pathophysiology
Although the exact cause of diabetic nephropathy is unknown, several mechanisms have been hypothesized. Hyperglycemia, the formation of advanced glycosylation products, activation of the renin-angiotensin- aldosterone system, and activation of cytokines are all thought to be contributing factors to the progression of disease.

Hyperglycemia appears to cause expansion and injury of the glomerular basement membrane of the kidneys by increasing the renal mesangial cell glucose concentration. Initially, the glomerular mesangium expands by cell proliferation and later by cell hypertrophy. Transforming growth factor beta (TGF-beta) is particularly important in causing the expansion and later fibrosis by stimulating the production of both collagen and fibronectin. Other cytokines that are present in the kidney are also under investigation for their role in diabetic nephropathy.

Advanced glycosylation products are formed as glucose binds reversibly—and eventually irreversibly—to proteins in the kidneys. The glycosylation products can eventually form complex cross-links over time as the hyperglycemia continues and can contribute to renal damage by stimulation of growth and fibrotic factors.

In diabetic nephropathy, the local renin-angiotensin system is activated. Angiotensin II is stimulated and results in constriction of the efferent arteriole of the glomerulus, which results in increased glomerular capillary pressures. Angiotensin II also stimulates renal mesangium expansion and fibrosis through activation of angiotensin II type 1 receptors, and increases the expression of TGF-beta and other growth factors.

Microalbuminuria (30-300 mg/L) may contribute to renal injury associated with diabetic nephropathy. An increase in glomerular permeability causes plasma proteins such as albumin to be secreted into the urine. A portion of these proteins is absorbed by the proximal tubular cells, which can trigger an inflammatory response that contributes to kidney damage. Macroalbuminuria (>300 mg/L), nephrotic syndrome, and eventually renal failure may occur during the later stages of diabetic nephropathy.

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