Article author: Dr. Riham Z Fardoun, Pharm.D. Pharmacy Doctor; Research and Teaching Assistant at the University of Houston, College of Pharmacy, Heart and Kidney Institute; Texas, United States.
Wednesday 15th March, 2006
It has been estimated that approximately 45 % of new patients
receiving dialysis in the United States are diabetics. Early
diagnosis of diabetes and early intervention are critical in
preventing the progression towards renal failure seen in many
type 1 and a significant percentage of type 2 diabetics.
The earliest clinical evidence of diabetic nephropathy is the presence of microalbumiuria, defined as the appearance of low but abnormal levels (greater than 300 mg in a 24-hour collection) of albumin in the urine. Clinically, diabetic nephropathy is characterized by a progressive increase in proteinuria and decline in GFR, hypertension, and a high risk of cardiovascular morbidity and mortality. Thus, the finding of microalbuminuria should trigger screening for possible vascular diseases and aggressive intervention to reduce all cardiovascular risk factors in patients with diabetes type 1 and 2.
The natural history of diabetic nephropathy is a process that
progresses gradually over years. Microalbuminuria typically
occurs after 5 years in type 1 diabetes, and ESRD develops in
50% of type 1 diabetics. On the other hand, type 2 diabetes has
a more variable course. Patients often present at diagnosis with
microalbuminuria because of delays in diagnosis and other
factors affecting protein excretion. Fewer patients with
microalbuminuria progress to advanced renal disease. Without
intervention, approximately 20% develop ESRD. However, because
of the high prevalence of type 2 compared to type 1 diabetes,
the majority of diabetics on dialysis are type 2 diabetics.
Many factors account for the pathophysiology in diabetic nephropathy. First, structural and anatomical changes in the kidney lead to increased glomerular capillary pressure in diabetes, and this increase is associated with hyperfiltration at the glomerulus. Second, glucose can induce the formation of advanced glycosylation end products (AGEs) by binding irreversibly to proteins in kidney and circulation. Over years these formed AGEs can stimulate growth and fibrotic factors, which contribute to the overall renal damage. Third, angiotensin 2, itself contributes to the progression of diabetic nephropathy by constricting the efferent arteriole in the glomerulus, and consequently leading to higher glomerular capillary pressures.
In screening for diabetic nephropathy, early testing for glucose intolerance and diabetes to identify patients who are at risk for developing microalbuminuria is recommended, particularly if they have other risks for type 2 diabetes such as hypertension, lipid abnormalities, or central obesity. Therefore, the presence of microalbuminuria should be performed at diagnoses in patients with type 2 diabetes. On the other hand, since microalbuminuria rarely occurs with short duration of type 1 diabetes, screening in individuals with type 1 diabetes should begin after 5 years? disease duration. Some evidence suggests that the prepupertal duration of diabetes maybe important in the development of microvascular complications. Therefore, clinical judgment should be exercised when individualizing these recommendations.
The goal of therapy in diabetic nephropathy involves multi-clinical approaches. One keystone in the prevention and management of diabetic nephropathy is tight glycemic control. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have proved that intensive diabetes therapy can significantly reduce the risk of the development of microalbuminuria and nephropathy in diabetic patients. The American diabetic association recommends an average hemoglobin A1c (HbA1c) value of 7 %.
In addition to glycemic control, blood pressure control is
the other keystone in prevention and treatment. The importance
of blood pressure control, no matter what agent is used, cannot
be emphasized enough in diabetes, both for slowing progression
of nephropathy and for preventing cardiovascular morbidity and
mortality. Currently, the most recent Joint National Committee
guidelines recommends that blood pressure in diabetics be
reduced to less than 130/80 mm Hg. It is important for
clinicians and patients to be aware early on that three or more
agents may be required to achieve the blood pressure goal, and
these agents will likely be needed long term. Angiotensin-converting
enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs)
are considered first line agents in patients with concomitant
hypertension and diabetes. In many cases, diuretics might be
added as second-line agents after angiotensin blockade in
diabetics. Dihydropyridines , a class of Calcium Channel
Blockers (CCB) may best be reserved as third- or fourth-line
agents in patients with diabetes, only after angiotensin
blockade and diuretics have already been instituted.
Other non-pharmacological approaches involve dietary restriction of protein intake. Dietary restriction of 0.8 g/kg/day in patients with overt nephropathy, or even 0.6 g/kg/day in the face of a falling GFR is recommended. In addition, it is important to maintain a low-sodium diet in diabetic nephropathy. Because many diabetics with renal disease are salt sensitive, minimizing salt intake can help in reaching blood pressure goals, with secondary benefits of decreased stroke risk, regression of left ventricular hypertrophy, and reduction in proteinuria. An advocated low-sodium diet of equal or less than 2.3 grams (5.8 grams of NaCl) or 100 mEq daily in patients with diabetes and either hypertension or any degree of proteinuria is recommended. Furthermore, avoidance of nephrotoxic agents, like Nonsteroidal antiinflammatory drugs (NSAIDs) and Radiocontrast media is advised. Lastly, Referral to a nephrologist should be considered if the GFR is steadily declining or is already below 60-70 ml/min.
In conclusion, annual screening for microalbuminuria in diabetic patients will allow the identification of nephropathy at an early stage. Improving glycemic control and aggressive antihypertensive treatment will slow the rate of progression of diabetic nephropathy. In addition, protein and salt restriction and the avoidance of nepthrotoxic drugs may have benefits in selected patients.
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