Complications of Diabetes Mellitus: Nephropathy

Diabetic nephropathy involves pathologic changes to the kidney vasculature. If uncontrolled, the disease progresses from microalbuminuria to macroalbuminuria and an elevated plasma creatinine concentration, and eventually to end–stage disease requiring dialysis or transplant. Pathogenesis involves hypertension, ischemia, hyperglycemia, and advanced glycosylation end products. Persistently elevated blood glucose, blood pressure, and cholesterol and triglyceride concentrations are associated with microalbuminuria.²⁴

Risk Factors

All individuals with diabetes are at risk for nephropathy. Pima Indians with type 2 diabetes have a particularly high susceptibility to nephropathy, with a 50% incidence after 20 years. However, Pimas living in the U.S. are at much higher risk, compared with Pimas in Mexico, suggesting that the risk among Pimas may be, in part, mediated by diet and lifestyle, rather than genetic factors. African Americans with type 2 DM appear to have more than 4 times the risk of end–stage renal disease, compared with Caucasians.²⁵ This may also be true for Native Americans and Mexican Americans.²⁶

Risk factors include:

• Family history of diabetes nephropathy.
• Poor blood glucose control.
• Concomitant hypertension.
• Elevated glomerular filtration rate.
• Dietary factors (see Nutritional Considerations below).

Other possible risk factors include obesity, increasing age, duration of DM, and smoking.

Diagnosis

Microalbuminuria, defined as a persistent loss of albumin in the urine of 30 to 299 mg/day, is the first indication of nephropathy. Macroalbuminuria is diagnosed when urinary albumin losses are ≥300 mg/day.

A random urine specimen with an albumin concentration of greater than 30 mg/L suggests microalbuminuria. False–negative or false–positive results may occur due to urine volume at time of collection.

A urine albumin/creatinine ratio with a value of 30 μg/mg or greater also suggests microalbuminuria.

Transient microalbuminuria may occur with hyperglycemia, exercise, heart failure, and febrile illness.

When screening suggests microalbuminuria, a repeat specimen (albumin/creatinine ratio) should be obtained after waiting at least 1 to 2 weeks. A standard urine test strip can usually detect macroalbuminuria (1+ or greater). Albumin–specific test strips can detect microalbuminuria. However, false–negatives and false–positives are possible when using test strips. Twenty–four hour urine samples are not required to make these diagnoses.

Treatment

Treatment recommendations for nephropathy are similar in type 1 and type 2 diabetes.

Glycemic control is essential for preventing further kidney damage.

Treatment with angiotensin–converting enzyme (ACE) inhibitors or/and angiotensin receptor blockers (ARBs) helps prevent the progression of microalbuminuria to more severe renal disease. This approach is especially important if hypertension is present, and target blood pressure to reduce vascular complications is less than 130/80 mmHg. Diltiazem, verapamil, and low–dose diuretics (because hypertension in diabetes is often volume dependent) may also be indicated.

Control of plasma cholesterol and triglyceride concentrations is important (see Hyperlipidemia for details on optimizing LDL, HDL, and triglycerides).

Weight loss is helpful, perhaps because of its beneficial effects on glucose, blood pressure, and lipid control.²⁷

Nutritional Considerations

Reducing saturated fat, cholesterol, and animal protein intake may reduce the risk for or progression of nephropathy. Elevated cholesterol is a risk factor for nephropathy28 and end–stage renal disease.²⁹ Cholesterol–lowering treatment was found to retard the progression of diabetic nephropathy.³⁰

Restriction of animal protein reduces the progression of diabetic nephropathy.³¹ Excessive intake of total protein and animal (not vegetable) protein has been shown to increase urinary albumin excretion.³² In short–term studies, proteinuria has been reduced through the use of vegetarian diets³³ and diets deriving protein primarily from soy and other plant sources.³⁴ These diets also facilitate blood pressure control,3 which further helps reduce diabetic nephropathy progression.³⁵

Dietary sodium restriction is indicated for a number of reasons, including prevention or treatment of microalbuminuria. It is also important because sodium excess may offset both the antihypertensive and antiproteinuric effects of renin–angiotensin system blocking drugs.³⁶