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Diabetic Nephropathy
Diabetes mellitus is responsible for approximately one-third of the cases of end-stage renal disease (ESRD) in the United States. Diabetic nephropathy is the most costly complication of diabetes mellitus. About 40% of patients with type 1 diabetes develop diabetic nephropathy. The incidence in type 2 diabetes is unclear, but many investigators believe that it is probably similar.
The risk factors for developing diabetic nephropathy in type 1 diabetics are genetic susceptibility, race, hypertension, and poor glycemic control. Targeting the last two risk factors is effective in preventing diabetic nephropathy or slowing its course.
Glomerular basement membrane thickening and mesangial expansion (diffuse glomerulosclerosis) are characteristic of diabetic nephropathy. It is important to know that functional and structural changes in the kidneys precede micro-albuminuria by about five years, and that microalbuminuria precede ESRD by more than ten years leaving ample time for intervention.
Microalbuminuria is defined as the excretion of 30-300 mg of albumin in a 24-hour urine collection. Urine dipstick is negative. Any amount of more than 300 mg constitutes overt proteinuria and urine dipstick becomes positive. Diabetics should be screened annually for the presence of microalbuminuria. Two positive tests for microalbumin out of three in a six-month period are diagnostic of microalbuminuria. Certain conditions (such as CHF, hematuria, UTI, fever, uncontrolled hypertension, and poor glycemic control) can increase urine albumin excretion, and therefore invalidate the results.
Treatment of hypertension is paramount in diabetic nephropathy. We should aim for blood pressure below 130/85 in diabetic patients. Angiotensin converting enzyme inhibitors (ACEI) are the agents of first choice due to their renoprotective and antiproteinuric effect that is independent of their antihypertensive effect. This appears to be a class effect.
Hyperkalemia can be particularly problematic in patients with advanced diabetic nephropathy on ACEI. A landmark study(1) comparing captopril with placebo in type 1 diabetics with diabetic nephropathy and serum creatinine <2.5 mg/dl demonstrated that captopril treatment was associated with a 50% reduction in the risk of the combined end points of dialysis, kidney transplantation and death.
In normotensive patients with type 2 diabetes, microalbuminuria, and serum creatinine <1.4 mg/dl, treatment with enalapril was associated with an absolute risk reduction of 42% for the development of diabetic nephropathy(2). A small study(3) in type 2 diabetics with diabetic nephropathy showed that atenolol had no effect on proteinuria, while lisinopril, verapamil SR, and diltiazem SR reduced proteinuria by 1.5-2 g/d at the end of the study.
Based on the limited available data it appears that calcium channel blockers (especially non-dihydropyridine) may have a renoprotective effect in diabetic nephropathy. Data are lacking regarding the renoprotective effect of angiotensin II receptor antagonists. Animal data are encouraging and human trials are ongoing.
Moderate protein restriction (0.6-0.8 g/kg/d) appears to be beneficial in slowing the progression of diabetic nephropathy(4). Patients should be carefully monitored for signs of protein malnutrition.
The DCCT trial(5) has demonstrated that intensive insulin regimens in type 1 diabetics reduced the occurrence of microalbuminuria by 39%, and that of proteinuria by 54% when compared with usual treatment.
Renal transplantation is the treatment of choice for ESRD secondary to diabetic nephropathy. Unfortunately, most patients are not transplant candidates, and their survival on dialysis is still poor (less than 20% survive more than 5 years).
References:
(1) Lewis et al: N Engl J Med 1993; 329: 1456-62
(2) Ravid et al: Arch Intern Med 1996; 156: 286-9
(3) Bakris et al: Kidney Int 1996; 50: 1641-50
(4) Pedrini et al: Ann Intern Med 1996; 124: 627-32
(5) DCCT investigators: N Engl J Med 1993; 329: 977-86
The risk factors for developing diabetic nephropathy in type 1 diabetics are genetic susceptibility, race, hypertension, and poor glycemic control. Targeting the last two risk factors is effective in preventing diabetic nephropathy or slowing its course.
Glomerular basement membrane thickening and mesangial expansion (diffuse glomerulosclerosis) are characteristic of diabetic nephropathy. It is important to know that functional and structural changes in the kidneys precede micro-albuminuria by about five years, and that microalbuminuria precede ESRD by more than ten years leaving ample time for intervention.
Microalbuminuria is defined as the excretion of 30-300 mg of albumin in a 24-hour urine collection. Urine dipstick is negative. Any amount of more than 300 mg constitutes overt proteinuria and urine dipstick becomes positive. Diabetics should be screened annually for the presence of microalbuminuria. Two positive tests for microalbumin out of three in a six-month period are diagnostic of microalbuminuria. Certain conditions (such as CHF, hematuria, UTI, fever, uncontrolled hypertension, and poor glycemic control) can increase urine albumin excretion, and therefore invalidate the results.
Treatment of hypertension is paramount in diabetic nephropathy. We should aim for blood pressure below 130/85 in diabetic patients. Angiotensin converting enzyme inhibitors (ACEI) are the agents of first choice due to their renoprotective and antiproteinuric effect that is independent of their antihypertensive effect. This appears to be a class effect.
Hyperkalemia can be particularly problematic in patients with advanced diabetic nephropathy on ACEI. A landmark study(1) comparing captopril with placebo in type 1 diabetics with diabetic nephropathy and serum creatinine <2.5 mg/dl demonstrated that captopril treatment was associated with a 50% reduction in the risk of the combined end points of dialysis, kidney transplantation and death.
In normotensive patients with type 2 diabetes, microalbuminuria, and serum creatinine <1.4 mg/dl, treatment with enalapril was associated with an absolute risk reduction of 42% for the development of diabetic nephropathy(2). A small study(3) in type 2 diabetics with diabetic nephropathy showed that atenolol had no effect on proteinuria, while lisinopril, verapamil SR, and diltiazem SR reduced proteinuria by 1.5-2 g/d at the end of the study.
Based on the limited available data it appears that calcium channel blockers (especially non-dihydropyridine) may have a renoprotective effect in diabetic nephropathy. Data are lacking regarding the renoprotective effect of angiotensin II receptor antagonists. Animal data are encouraging and human trials are ongoing.
Moderate protein restriction (0.6-0.8 g/kg/d) appears to be beneficial in slowing the progression of diabetic nephropathy(4). Patients should be carefully monitored for signs of protein malnutrition.
The DCCT trial(5) has demonstrated that intensive insulin regimens in type 1 diabetics reduced the occurrence of microalbuminuria by 39%, and that of proteinuria by 54% when compared with usual treatment.
Renal transplantation is the treatment of choice for ESRD secondary to diabetic nephropathy. Unfortunately, most patients are not transplant candidates, and their survival on dialysis is still poor (less than 20% survive more than 5 years).
References:
(1) Lewis et al: N Engl J Med 1993; 329: 1456-62
(2) Ravid et al: Arch Intern Med 1996; 156: 286-9
(3) Bakris et al: Kidney Int 1996; 50: 1641-50
(4) Pedrini et al: Ann Intern Med 1996; 124: 627-32
(5) DCCT investigators: N Engl J Med 1993; 329: 977-86
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