Diabetic Nephropathy

Diabetic nephropathy is one of the most common complications of diabetes.

First of all, diabetes is very common life long disease , By the year of 2025, the number of diabetic patients will be doubled, Diabetes is a worldwide disease, affecting all parts of the world.

Complications of diabetes affect every part of the body.

We have 2 types of complications:

1. Microvascular Complications: which affects the retina (retinopathy), the kidney (nephropathy), and the nerves(neuropathy).

2. Macrovascular complications: responsible for the coronary artery disease and peripheral artery disease.

v  Diabetic nephropathy is the most common complication of diabetes and the leading cause of mortality.

Diabetes is the most common cause of CKD (chronic kidney disease).

Each year in USA, between 12,000 & 24,000 people lose their sight as a result of diabetes.

Prevalence of diabetic nephropathy:

30-40% of type I DM develop nephropathy.

5-60% of type II DM (depending on ethnic origin) :   Caucasians 5-10%

                                                                                             African-Americans 60%

Around 50-60% of patients on dialysis are due to diabetic nephropathy, another 30-40% are due to hypertension, and the rest are due to all other causes.

So, treating DM and HTN properly will save a lot of lives.

v  Diabetes and renal disease:

Peak onset of nephropathy is between 10-15 years after diagnosis of the disease.

Not all diabetic patients will develop nephropathy.

Those without proteinuria, after 20-25 years of the disease, have  a risk of 1% per year  of developing nephropathy(very low risk).

v  Predictors of diabetic nephropathy:

Smoking, proliferative diabetic retinopathy, eye disease, laser therapy

The most predictive single factor to increased likelihood of diabetic nephropathy is proliferative diabetic retinopathy. So, It is very important to ask patients that have diabetes if they have any problems in the eye.

v  Predictors of diabetic nephropathy in families with diabetes:

Microalbuminuria, hypertension( in most cases, diabetic patients with nephropathy have hypertension), glucose control(most important to prevent microvascular complications), duration of DM II, familial disposition.

v  Risk  factors in DM:

	uncontrollable	Controllable
Nephropathy	Ethnic group	Glucose
		BP
		Hyperlipidimia
		weight
Retinopathy	Disease duration
	Type I disease
	Pregnancy?
nephropathy	Disease duration
	Ethnicity
	Genetic

v  Risk factors:

1.      Genetic susceptibility

There is an increased incidence if diabetic siblings or father had nephropathy.

ACE gene of DD polymorphism is risky more than Di or ii.

Nephropathy is familial. The risk of nephropathy is x5 if a sibling has nephropathy.

Family hx of HTN also increases the risk of nephropathy.

2.      Glycemic control: early control is the most important factor, because if the microvascular events have started, controlling sugar will not stop the process.

Increased level of HbA1c increases the risk to develop nephropathy.

Glycemic control affect microvascular complications more than macrovascular complications.

3.      Race

4.      Blacks, Mexican-Americans,

5.      Smoking:

-          Increases risk of nephropathy 8 times

-          Increase rate of progression

-          Increase mortality by a factor of 100

-          So, even after the onset of nephropathy, you can convince your patients to stop smoking to prevent the progression of disease and to decrease mortality.

6.      Uncontrolled B.P

7.      50% of type I patients have GFR 25-50% above normal within 5 years

It increases nephropathy by x8. Increase progression. Increases cardiac mortality of one hundred.

v  Natural history of diabetic nephropathy:

  we have 5 stages for the development of diabetic nephropathy.

	Characteristic	GFR	Albumin excretion	Hyertension
1.      Hyperfiltration & hypertrophy of glomeruli	Glomerular hypertension	Increased in type I & II DM	May be increased or normal	Type I à normal Type II à normal                          or increased
2.      Silent stage	Thickening of basement membrane	Goes back to normal	May be normal	normal
3.      Recepient			microalbuminuria	Start to appear
4.      Overt diabetic nephropathy		Starts decreasing	Macroalbuminuria (overt diabetic nephropathy)	Most patients have HTN
5.      uremia	End stage reanal disease	less than 15 ml/min		Patients have HTN

Timing of stages: Stage 2 occurs between 2 and 15 years, stage 3: about 10-15 years, stage 4: between 15-20 years. These durations might vary depending on other risk factors (e.g. smokers with uncontrolled hypertension deteriorate faster than those without these risk factors). The rate of decline in GFR is about 1ml/min per month, and 50% of patients reach end stage renal disease within 7 to 10 years after the onset of overt proteinuria (decline of 1 ml/min per month or 12 ml/min per year or about 80 ml/min in seven years). Note that if the decline in GFR is more rapid than you would expect, other causes should be suspected (e.g. neurogenic bladder causing obstructive uropathy, infection, papillary necrosis, etc.)

v  Pathogenesis:

Starting with theory that was mentioned yesterday; if afferent arteriole is constricted, then both the GFR and renal plasma flow are decreased (due to decreased intra-glomerular capillary pressure), while constricting the efferent arteriole results in increasing the GFR while reducing renal plasma flow. So glucose per se (or of course hyperglycemia) and advanced glycation products both increase GFR. Insulin secretion leads to vasoconstriction of the afferent arteriole, so with insulin deficiency in diabetes, then the afferent arteriole would dilate and hyperfiltration occurs. Prostaglandins and thromboxanes might also play a role. The renin-angiotensin axis also plays an important role because angiotensin II constricts both but mainly the efferent arteriole and that would also increase the intra-glomerular capillary pressure and hyperfiltration. Nitric oxide is also very important.

v  Hyperglycemia, in addition to genetic factors, hypertension, hyperlipidemia and smoking, leads to tissue damage. There are several pathways or mechanisms that are incriminated in the development of hyperglycemia-induced tissue damage:

1. Increased polyol pathway flux.
2. Increased advanced glycation end products.
3. Activation of protein kinase C (PKC).
4. Increased hexosamine pathway flux.
Moreover, mitochondrial reactive oxygen species might also play a role. Probably, activation of PKC is the most important, but all will lead to microvascular damage resulting in neuropathy, retinopathy and nephropathy. Therapies targeted at these pathways were found to be too toxic for human use.
So, hyperglycemia would increase angiotensin II levels and both also increase PKC which will increase transforming growth factor β1 (TGF-β1) which is responsible for inducing fibrosis and sclerosis in the glomeruli. So the more severe is the hyperglycemia, the more activated is this pathway. So, ACE inhibitors and Angiotensin receptor blockers is very important.

v  Prevention

Regular screening of diabetics for nephropathy, usually by urinalysis, or more specifically by urine dipstick. Normally, albumin secretion is less than 30 mcg/mg of creatinine. Microalbuminuria is between 30 and 299 mcg/mg of creatinine and macroalbuminuria (overt) is equal or more than 300mcg/mg of creatinine.
Type one diabetics should start screening for nephropathy after 5 years of the diagnosis. While type 2 are screened initially when diagnosed with diabetes and then this is repeated annually.

v  Management:

The recommendations for diabetic nephropathy are very good blood pressure control.

v  Hyperglycemia, along with hypertension, hyperlipidemia, smoking and genetics all interact to cause kidney tissue damage.

Hyperglycemia à protein kinase c activation à microvascular damage à neuropathy, retinopathy and neuropathy.

Hyperglycemiaà   angiotensin II  à    PKC à TGF-β1 à glomerular sclerosis

So preventing angiotensin 2 by using ACEI or ARBs would reduce PKC production and ultimately lead to less glomerular sclerosis.

v  No study have shown that these medications (ACEI/ARBs) prevent the development of microalbumenuria, however, giving these medication once patient have developed microalbumenuria might prevent transformation to overt protienuria.

v  Treatment recommendations for diabetic nephropathy:

·         Bp. Control 130/80

·         Glucose control Hb A1C below 7%

·         Lipid control LDL<100

·         Careful monitoring of :

-          Ca and phosphate

-          Hepertension