Diabetic Nephropathy

 Diabetic Nephropathy

 

Diabetic Nephropathy

•  Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/d or >200 mcg/min) that is confirmed on at least 2 occasions 3-6 months apart, a relentless decline in the glomerular filtration rate (GFR), and elevated arterial blood pressure.
• Diabetic nephropathy is the leading cause of chronic renal failure in the United States.
• Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States .
• is a metabolic disorder of mDiabetes ultiple causes characterized by chronic hyperglycemia and disorders of carbohydrate, fat, and protein metabolism. Results from defects in insulin secretion (type 1), insulin action (type 2), or combination of these factors. 
• Diabetic nephropathy rarely develops before 10 years' duration of IDDM. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years.

Patho-physiology :

Scientists have described five stages in the progression to kidney failure in people with diabetes.

Stage I

   Increase the flow of blood through the kidneys, and through the glomeruli, this increases-called hyperfiltration--and the kidneys are larger than normal. Some people remain in stage I indefinitely; others advance to stage II after many years. 

Stage II

The rate of filtration remains elevated or at near-normal levels, and the glomeruli begin to show damage. Small amounts of a blood protein known as albumin leak into the urine--a condition known as microalbuminuria. 

    When albumin loss increases from 20 to 200 micrograms per minute, the finding of microalbuminuria becomes more constant. (Normal losses of albumin are less than 5 micrograms per minute.) 

    People with type 1 and type 2 diabetes may remain in stage II for many years, especially if they have good control of their blood pressure and blood glucose levels. 

Stage III

The loss of albumin and other proteins in the urine exceeds 200 micrograms per minute. It now can be detected during routine urine tests.

    Stage III sometimes is referred to as "clinical albuminuria" or "overt diabetic nephropathy"). 

    Some patients develop high blood pressure. 

    The kidneys progressively lose the ability to filter waste, and blood levels of creatinine and urea-nitrogen rise. People with type 1 and type 2 diabetes may remain at stage III for many years. 

Stage IV

    This is referred to as "advanced clinical nephropathy." The glomerular filtration rate decreases to less than 75 milliliters per minute, large amounts of protein pass into the urine, and high blood pressure almost always occurs. Levels of creatinine and urea-nitrogen in the blood rise further. 

Stage V

• The final stage is kidney failure. The glomerular filtration rate drops to less than 10 milliliters per minute. Symptoms of kidney failure become apparent. 
• These stages describe the progression of kidney disease for most people with type 1 diabetes who develop kidney failure. 
• For people with type 1, the average length of time required to progress from onset of kidney disease to stage IV is 17 years. 
• The average length of time to progress to kidney failure is 23 years. 
• Progression to kidney failure may occur more rapidly (5-10 years) in people with untreated high blood pressure. 
• If proteinuria does not develop within 25 years, the risk of developing advanced kidney disease begins to decrease. 

EFFECTS OF HIGH BLOOD PRESSURE :

• hypertension, is a major factor in the development of kidney problems in people with diabetes. Hypertension also accelerates the progress of kidney disease where it already exists.
• people with diabetes must keep their blood pressure at 130/85 or lower and people with renal insufficiency (proteinuria greater than 1 gm/24 hrs)  must keep their blood pressure at 125/75 or lower.
• Early detection and treatment of even mild hypertension are essential for people with diabetes.

CLINICAL :

• Generally, diabetic nephropathy is considered after a routine urinalysis .Patients usually have physical findings associated with long-standing diabetes mellitus. 
• Hypertension .
•  Evidence of diabetic retinopathy  .
•  Peripheral vascular occlusive disease (decreased peripheral pulses, carotid bruits).
•  Evidence for diabetic neuropathy .
•  Evidence for fourth heart sound during cardiac auscultation .
• Non-healing skin ulcers/osteomyelitis .

INVESTIGATION :

Urinalysis

•   o Regular annual urinalysis is recommended for screening for microalbuminuria Typically, the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL, glucosuria, and occasional hyaline casts.
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•   o A 24-hour urinalysis for urea, creatinine, and protein is extremely useful in quantifying protein losses and estimating the GFR.

Imaging Studies :

Renal ultrasound

•  Observe for kidney size, which is usually normal to increased in the initial stages and, later, decreased or shrunken with chronic renal disease.
•  Rule out obstruction.
•  Perform echogenicity studies for chronic renal disease.
• Renal biopsy is not routinely indicated in all cases of diabetic nephropathy, especially 

TREATMENT :

• Glycemic control
• Antihypertensive treatment
• Dietary protein intake
• Renal replacement therapies
• Activity

Antihypertensive treatment :

• antihypertensive treatment attenuates the rate of decline in renal function in patients who have IDDM, hypertension, and proteinuria. 
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• Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood pressure and the urinary albumin excretion rate in NIDDM patients who have microalbuminuria.
• ACE inhibition delays the development of diabetic nephropathy 
• Study show that normotensive patients with microalbuminuric NIDDM received enalapril or placebo for 5 years. 
• Of these patients, 12% in the actively treated group experienced diabetic nephropathy, with a rate of decline in kidney function of 13%, and 42% of the patients receiving placebo experienced nephropathy.
• Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood pressure and albuminuria and protects kidney function in patients with hypertension, IDDM, and nephropathy. 
• Beneficial effects on kidney function have also been reported in patients with normotension, IDDM, and nephropathy. 
• Meta-analysis has shown that ACE inhibitors are superior to beta-blockers, diuretics, and calcium channel blockers in reducing urinary albumin excretion in normotensive and hypertensive IDDM and NIDDM patients. 

NUTRITIONAL TREATMENT :

Dietary protein intake: 

•     A meta-analysis examining the effects of dietary protein restriction (0.5-0.85 g/kg/d) in diabetic patients suggested a beneficial effect on the GFR, creatinine clearance, and albuminuria.. 
• When nephropathy is advanced, the diet should reflect the need for phosphorus and potassium restriction, with the use of phosphate binders.

Carbohydrates :

• Carbohydrates are commonly referred to as sugar, starch, and fiber. 
• We obtain carbohydrates typically from grains, fruits, vegetables, and dairy products. 
• low glycemic index diets may have other health benefits, most experts agree that eating a combination of these sugars as they are normally found in most foods is more important than trying to isolate and monitor each one in an effort to improve your health through complex meal plans.

Starches :

• Starches are complex carbohydrates from plant sources. Potatoes and legumes (such as peas and beans) are some examples of starches .
•  However, there are some starches (such as those found in kidney and black beans, peas, and lentils) that humans are unable to break down into glucose. 
• These are called resistant starches. This type of starch does not increase the blood glucose level. 
• In fact, if you replace digestible starch with resistant starch in a meal, you will have a lower glucose level and a lower insulin level than you'll have if you ate mainly digestible starch

Fiber :

• vegetables, fruits, and whole grains dietary .fiber intake needs to be significantly higher (nearly double) than what's required for the general population. recommends 20 to 35 grams of fiber per day. 

Sweeteners :

• Foods that contain sucrose can increase your blood glucose level significantly, but calorie for calorie no more so than other starches. 
• It has been suggested that fructose be used in place of sucrose in the diet. However, studies have shown that when fructose is substituted for sucrose, it may increase cholesterol levels. Therefore, it is not recommended that fructose be specifically substituted for sucrose. 
• However, you shouldn't avoid consuming naturally occurring fructose in foods such as fruits and vegetables.

Fat and Cholesterol :

• Fat and cholesterol limitation should be a primary goal in the diets of all people with diabetes. Specifically, saturated fats should be limited to less than 10 percent of the total calories in the diet because they are the primary cause of increased LDL. 
• People with diabetes appear to be more affected by dietary cholesterol than those without diabetes. 
• It is recommended that the amount of cholesterol in the daily diet be no more than 100 mg/dl.
• Diet low in saturated fats and cholesterol leads to improvements in total cholesterol, a decrease in (LDL), in triglycerides . 
• If this type of diet is used in conjunction with exercise, it can significantly increase these benefits. 
• Fat and cholesterol limitation should be a primary goal in the diets of all people with diabetes. Specifically, saturated fats should be limited to less than 10 percent of the total calories in the diet because they are the primary cause of increased LDL. 
• People with diabetes appear to be more affected by dietary cholesterol than those without diabetes. 
• It is recommended that the amount of cholesterol in the daily diet be no more than 100 mg/dl.
• Diet low in saturated fats and cholesterol leads to improvements in total cholesterol, a decrease in (LDL), in triglycerides . 
• If this type of diet is used in conjunction with exercise, it can significantly increase these benefits. 

Trans-unsaturated fats, or trans-fatty acids :

• come from processed vegetable oils commonly found in margarine and fast foods such as French fries.
•     This type of fat has properties similar to saturated fat; that is, it raises LDL cholesterol levels, It also decreases (HDL). 
•     Therefore, you should consume trans-unsaturated fats sparingly. 
• come from processed vegetable oils commonly found in margarine and fast foods such as French fries.
•     This type of fat has properties similar to saturated fat; that is, it raises LDL cholesterol levels, It also decreases (HDL). 
•     Therefore, you should consume trans-unsaturated fats sparingly. 

Sterols and stanols :

•    which are substances from plants, are compounds that can be used to restrict the absorption of cholesterol from your gastrointestinal tract into your blood. These work because their structure is very similar to cholesterol and they bind to cholesterol transport on cells in the intestine, but they are not absorbed into the blood. Thus, the more stanols or sterols that bind to the transporters, the less cholesterol will be absorbed into the blood. 
•    The recommended amount of stanols is 3.4 grams per day; for sterols, it is 1.3 grams per day. 
•    These are typically available in concentrated forms such as spreads, since they are present in such low amounts in normal servings of fruits and vegetables. Benecol margarine contains stanols.

FOOD PYRAMID :

• There are multiple food pyramids that are based on the USDA's Food Guide Pyramid. 
• The USDA's Food Guide Pyramid is designed to help you balance your meals in a healthy manner. 
• The types of food you should eat less of appear at the top of the pyramid, and those you should eat more of are on the bottom.
• Make sure that you eat more foods from the bottom of the pyramid (that is, fruits, vegetables, and whole grains) than from the top of the pyramid (such as fats and sweets). 
• The foods from the bottom of the pyramid are less dense in calories and usually contain less fat as well. 
• As you progress up the pyramid, the food becomes denser with calories-not to mention tougher to resist.
• If I eat more foods from the bottom of the food pyramid early in a meal, I consume fewer foods from the top of the food pyramid..

Determining Your Caloric Needs :

• How many calories you need. 
• There are multiple ways to do this, and these are all dependent on your health, weight, activity level, and goals.
• If you are overweight, then you will likely be given a diet plan that gives you a negative energy balance. 
• If you are already doing a considerable amount of exercise, the focus of your plan will likely be reducing the number of calories consumed.
• Say that you are currently overweight and consuming 2,000 calories per day. 
• However, if you have a BMI of 50 (severely obese) and have been consuming upwards of 4,000 calories per day, an 1,800-calorie diet would be a 2,200-calorie deficit. This would be classified as a very low-calorie diet and would require close medical supervision because of the rapid weight loss and other metabolic changes that would occur.

Drugs used in Clinical Trials for Diabetic Nephropathy :

• ACE inhibitors,ARB, HMG-CoA reductase inhibitors, vitamins - This study is currently recruiting patients (Current: 23 Nov 2006) 
• Addition of furosemide 20 mg oral bid to baseline regimen - This study is currently recruiting patients (Current: 23 Nov 2006) 
• Aliskiren - Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria - This study is currently recruiting patients (Current: 23 Nov 2006) 
• Candesartan - Angiotensin II Antagonism of TGF-Beta 1 - This study has been completed (Current: 23 Nov 2006) 
• Celecoxib - Treatment of Diabetic Nephropathy - This study is currently recruiting patients (Current: 23 Nov 2006) 
• Daglutril - Study to Evaluate the Efficacy and Safety of Daglutril Compared to Placebo on Top of Losartan in) 
• Folic Acid - Nitric Oxide (NO) Activity and Diabetic Nephropathy - This study is currently recruiting patients (Current: 23 Nov 2006) 
• Pyridorin (pyridoxamine dihydrochloride) - Effect of Pyridorin in Patients With Diabetic Nephropathy - This study has been completed (Current: 23 Nov 2006) 
• Soy Protein - Soy Protein in Early Diabetic Nephropathy - This study has been completed (Current: 23 Nov 2006) 
• Spironolactone - Spironolactone in Diabetic Nephropathy - This study has been completed (Current: 23 Nov 2006) 

FUTURE TREATMENT OF DIABETIC NEPHROPATHY :

• Potential of the ACE/ARB combination 
• Marketing rationale for the ACE/ARB combination
• Renin inhibition: what are the therapeutic opportunities? 
• New compounds should target the underlying disease 
• New approaches for diabetic microvascular complications 

Researches about future treatment of Diabetic Nephropathy :

•  Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis
• Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. 
• Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. 

2- Anti-CTGF therapy :

• Connective tissue growth factor (CTGF) is barely detectable in normal kidneys but increases in kidney disease..
• In early stage kidney disease, CTGF is directly upregulated by pathogenic conditions .CTGF continues to play a key role in mediating the structural damage caused by proteinuria and in accelerating progression to ESRD by acting as a downstream mediator of the chronic fibrotic effects of transforming growth factor-beta (TGF-beta).
• Anti-CTGF therapy: new approach to treating diabetic nephropathy In addition, administration of anti-CTGF therapy during the early stages of diabetic nephropathy may help prevent the onset of, or reduce the severity of, cardiovascular diseases and retinopathy, which frequently accompany progression to ESRD. 

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