Detecting and controlling diabetic nephropathy: What do we know?

Tight glycemic control reduces nephropathy, but does it increase cardiovascular risk?

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.