Detecting and controlling diabetic nephropathy: What do we know?

Proteinuria—the best marker of disease progression

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.