Diabetic Nephropathy

Diabetic nephropathy is the most common cause of renal failure, accounting for more than half of all cases of end-stage renal disease in the United States.  (End-stage renal disease means that the patient requires renal replacement with either dialysis treatment or a kidney transplant).  Kidney disease will affect between 20-40% of diabetics in their lifetime. Diabetic nephropathy involves steadily increasing proteinuria, accompanied by elevated blood pressure, with a progressive decline in GFR. Diabetics with kidney disease also have a greatly increased risk of cardiovascular disease.

Proteinuria is both a consequence of the glomerular damage in diabetes mellitus, and a cause of further damage, since it leads to inflammation and fibrosis in the renal tubules and a loss of functional nephrons. A specific assay for the small blood protein albumin is a more sensitive test to determine proteinuria than is a typical urine dipstick test for protein. If high values are measured, this is termed albuminuria. The table below gives values that are used to define moderately increased albuminuria (a precursor to diabetic nephropathy) and established disease.

Albumin Albumin-creatinine ratio (ACR)*
normal 20 mg/day less than 30 mg/g
moderately increased albuminuria 30-300 mg/day 30-300 mg/g
severely increased albuminuria
greater than 300 mg/day greater than 300 mg/g
*Because of the inconvenience of 24 hour urine collection, a spot urine collection (ideally obtained first thing in the morning) can be used and the urinary albumin to creatinine ratio is determined. Finding the ratio to creatinine avoids the confounding effects of variations in urine volume.

In its early stages, diabetic nephropathy does not cause symptoms. Patients who have been diagnosed with diabetes mellitus are screened for albuminuria, so that they can be treated.  Drugs that reduce angiotensin II signaling are helpful in reducing proteinuria (see below).

Changes in the Glomerulus

Diabetic nephropathy causes characteristic changes to the structure of the glomerulus known as glomerulosclerosis. In glomerulosclerosis, there are increased extracellular deposits inside the renal corpuscle, with a decreased surface area available for filtration. The glomerular basement membrane becomes thicker, yet more leaky.  Historically, these changes had been attributed to effects on endothelial cells and mesangial cells, the cells that support the capillary loops. However, more recent research suggests that effects on podocytes may be the most important factor in causing diabetic glomerulosclerosis.

Diabetic nephropathy can cause a disruption of the podocyte cytoskeleton, which results in a change in shape known as podocyte effacement.  As well, diabetic nephropathy may cause the loss of podocytes.  The most important consequence of these changes in the glomerulus is that they cause a leaky filtration membrane, so there is abnormally increased filtration of protein.  Proteinuria then causes damage to the renal tubules and further loss of nephrons.

Pathogenesis of Diabetic Nephropathy

The precise factors that are responsible for diabetic nephropathy are still being determined. In diabetes mellitus, two changes occur:

Hyperglycemia causes there to be abnormal glycosylation (glycation) of cellular proteins, and through a series of chemical reactions, these evolve to form what are known as advanced glycation end-products (AGEs). AGEs can induce abnormal cellular changes by signaling through a receptor (known as RAGE), which is expressed by cells in the glomerulus. This abnormal signaling may act to disrupt important paracrine signaling between podocytes and endothelial cells required for normal maintenance of the filtration membrane. It can also cause abnormalities in extracellular proteins, thus perhaps affecting the glomerular basement membrane and the connective tissue supporting the capillary loops. Hyperglycemia may also stimulate the formation of oxygen radicals that can further damage cells.

Insulin signaling may be required for both the survival of podocytes, and for the maintenance of proper podocyte structure. In a very elegant experiment, investigators specifically eliminated the insulin receptor from podocytes in mice. These mice developed proteinuria and glomerulosclerosis in the absence of hyperglycemia. Examination of the glomerulus with electron microscopy revealed changes in the architecture of the podocytes and thickening of the glomerular basement membrane. Tests also revealed evidence of podocyte apoptosis. This data shows that the changes of glomerulosclerosis can occur in response to a decrease in insulin signaling that is specific to podocytes.

Treatment of Diabetic Nephropathy

Naturally, treatment to limit progression of diabetic nephropathy involves good glycemic control and good blood pressure control. Clinical trials have shown that drugs that reduce signaling by angiotensin II are able to reduce proteinuria and slow the progression of diabetic nephropathy. These drugs include ACE inhibitors and angiotensin II receptor blockers. These drugs appear to provide renal protection that goes beyond their beneficial effect on blood pressure. This may be due to the fact that there are intrarenal effects of angiotensin II, in addition to its effects on peripheral resistance or its stimulation of aldosterone secretion and the regulation of ECF volume. Angiotensin II preferentially causes constriction of the efferent arteriole, which increases pressure in the glomerular capillaries and would promote more filtration of protein. As well, angiotensin II affects expression of important proteins in the filtration membrane, and it also has pro-inflammatory effects. Thus, reducing angiotensin II signaling helps to preserve the filtration membrane and limit proteinuria.

The recent data showing the importance of insulin signaling in podocytes supports the idea that treatment of diabetics with insulin-sensitizing drugs (metformin and thiazolidinediones) may better slow the progression of diabetic nephropathy, but this has yet to be tested.

Further Reading (optional)

These are references for the recent study about the effects of insulin signaling in podocytes, and an accompanying comment paper. The links are to the Pubmed citations.

Off-campus access: open LINK TO PROXY SERVER. Next, type in the URL's given above.

Quick Quiz

Fill-in Answer Correct False Correct Answer
1. Name the small blood protein whose levels are measured as a more sensitive assay for proteinuria in diabetic kidney disease.
2. Name the term for the characteristic changes that occur in the renal corpuscle with diabetic nephropathy.
3. Changes in the shape and structure of these cells are an important cause of a leaky filtration membrane.
4. Drugs that reduce or block this signaling molecule are useful in the treatment of diabetic nephropathy.

(Spelling must be correct)