Diabetic Nephropathy

This is a common rnicrovascular complication of type one and two diabetes. It is clinically defined by the presence of >500 mgs proteinuria 124 hours. A positive albustix Dipstix test is equivalent to a concentration of urinary protein (chiefly albumin) of 300mgsL. In it's florid form a typical nephrotic syndrome occurs, in which there is>3 gms protein, oedema, and hypoalbuminemia. In the untreated,uncontrolled patient this will lead inevitably to chronic renal failure within 5 to 6 years.Glornerular

Renal Structure and function

KM Sliaw Diabetic Co.mpllcations

capillary tuft

Pathogenesis of Diabetic Nephropathy

Early Phase
This is a silent phase clinically. A variable period after development of diabetes, some individuals develop an increase in glomerular filtration rate; good glucose control has been shown to bring this hyperfiltration back to normal values. Renal size also increases. Nornlally the capillaries do not allow the leakage of albumin. Two factors pennit this to happen. Firstly the BM of the glomemlar capillaries, change their physical properties and the negative charge normally present on the membrane is lost.This negative charge repels albumin which is also negatively charged. The above - changes of hyperfiltration, and BM changes promote leakage of albumin from the glomerulus.

Late Phase: Clinical Nephropathy

Clinical phase of nephropathy is established when persistent proteinuria >500 mgs/day (quantitative), is demonstrated, or the presence of 1-1- proteinuria (semi-quantitative), which corresponds to an albumin excretion rate (AER) greater than 300mgs/day, or 200mcg/ min). At this time most patients are hypertensive, and virtually all become so as time goes on. In the past end stage renal failure occurred approximately 5 to 7 years after the onset of macro-proteinuria.

Hyperkalernia is common in diabetic nephropathy as a result of a renal tubular defect in which low renin, low aldosterone levels promote potassium retention even in the absence'of renal failure. Hence when several potassium retaining medications are used together, care should be taken to monitor potassium levels.Retinopathy is present in virtually all patients with nephropathy, but the reverse is not true, i.e., not all patients with retinopathy have renal disease.When one is coilfronted with a diabetic with renal failure or proteinuria, one needs to consider the possibility of non-diabetic renal disease. The presence of hematuria, red cell casts, absence of retinopathy and shrunken kidneys on imaging by ultrasound are pointers to non-diabetic renal disease. These patients need to be investigated to find out the cause of renal disease so that appropriate treatment can be offered. This is in contrast to diabetics with typical diabetic nephropathy (who have retinal changes,normal or large kidneys, and no hematuria) who do not require further investigations.

End Stage Renal Disease

As mentioned earlier this occurs almost inevitably five to seven years after macro-proteinuria sets in.Fluid retention occurs early, compounded by concomitant cardiac failure. Once pulmonary edema occurs the prognosis is poor. Peripheral neuropathic symptoms could worsen when uremic neuropathy contributes to symptoms.A patient in end stage renal failure is likely to have any or all of the macro and micro vascular complications, as well as infections.

Management of Diabetic Nephropathy

Early CZi~tical Phase

Early detection of micro-albuminuria is now considered to be very important in the clinical care of a diabetic patient, because at this stage, it may be possible to prevent the progression to end-stage renal failure.Micro-albuminuria is measured by an imrnunochemical method. Albumin excretion is expressed as an excretion rate (mg/24 hr); albumin excretion of >300mgs/24 hours areabnormal. Alternatively albuminJcreatinine ratio (mglmmol) can be used in an early morning urine collection. A value of >3.5 mglmmol is abnormal.

Persistent micro-albuminuria is a sign of cardiovascular and early renal disease.*~t felt that if aggressively treated at this stage, then renal failure can be averted.However, micro-albuminuria is often intermittent, and in type two diabetics the natural history of micro-albuminuria has not been clearly established. Hence, in type one diabetes there is a clear recomtnendation to test annually for ~nicroalbuminria in patients over the age of 12 years and a duration of diabetes exceeding five years. For type two diabetes such screening is not mandatory at the current state.

The use of ACE-inhibitors has been shown to be highly effective. The basis of the action of ACE-inhibitors is as follows:

ACE-inhibitors preferentially dilate th'e efferent arteriole of the renal glometvlus as shown below diagrammatically:
 

Glomerular capillary loop glomerular capillary loop before ACE-inhibitors after ACE-inhibitors

This effect on the efferent arteriole decreases the intraglomerular filtration pressure,and helps to reverse the micro-albuminuria.
The dose of ACE-inhibitors is titrated according to the blood pressure which is recommended to be kept at or below 130180 mm Hg.
 

Effect of the ACE-inhibitors on Arteriole of tlie Renal Glomerulus

Late Clinical Phase

ACE-inhibitors must continue to be used even aftcr macro-proteiuria has occurred.Once renal failure or hyperkale~nia occurs then they must be discontinued.Hypertension must be controlled meticulously. Clinical research has shown that control of hypertension is reno-protective. The choice of anti-hypet-tensives other than ace-inhibitors is dictated by the presence of other co-morbid complications.
 

Thus if there is IHD, then beta-blockers must be used in conjunction with ace-inhibitors, In asthmatics, beta-blockers will need to be replaced by amlodepine (avoid nifedepine due to effect of tachycardia).