Dr. S.M.Sadikot.
Hon. Endocrinologist,
Jaslok Hospital and Research Centre,
Mumbai 400026

Renal dysfunction is fairly common in people with diabetes. Approximately 25% to 40% of patients with Type 1 diabetes ultimately develop diabetic nephropathy (DN), whilst the corresponding figures for Type 2 diabetes are in 5% to 15% although some studies show that the figure may go as high as 40% even in this category of patients. Diabetic nephropathy (DN) progresses through about five predictable stages. Progression through these five stages is rather predictable because the onset of DM 1 can be identified, and most patients are free from age-related medical problems. The time line for Type 2 patients is not too clear as the onset can be quite insiduos and some patients progress through the stages very rapidly.

Stage 1 (very early diabetes) Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR).

Stage 2 (developing diabetes) The GFR remains elevated or has returned to normal, but glomerular damage has progressed to significant microalbuminuria (small but above-normal level of the protein albumin in the urine). Patients in stage 2 excrete more than 30 mg of albumin in the urine over a 24-hour period. Significant microalbuminuria will progress to end-stage renal disease (ESRD). Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis.

Stage 3 (overt, or dipstick-positive diabetes) Glomerular damage has progressed to clinical albuminuria. The urine is "dipstick positive," containing more than 300 mg of albumin in a 24-hour period. Hypertension (high blood pressure) typically develops during stage 3.

Stage 4 (late-stage diabetes) Glomerular damage continues, with increasing amounts of protein albumin in the urine. The kidney's filtering ability has begun to decline steadily, and the levels of blood urea and serum creatinine have begun to increase. The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage 4.

Stage 5 (end-stage renal disease, ESRD) GFR has fallen to approximately 10 milliliters per minute (<10 mL/min) and renal replacement therapy (i.e., hemodialysis, peritoneal dialysis, kidney transplantation) is needed.

Why is renal dysfunction so common in patients with diabetes? Poor glycemic control, hypertension, dyslipidemias are the major predisposing factors to renal dysfunction in a person with diabetes. Genetics also play an important role: Patients who have one or two deletions of the angiotensin-converting enzyme (ACE) gene, a defect in the sodium proton pump, or a family history of hypertension are at increased risk for progression to diabetic nephropathy. However in such patients renal dysfunction does not occur until diabetes develops; the worse and more prolonged the hyperglycemia, the greater the risk of diabetic nephropathy.

Whilst some people feel that renal dysfunction is a part and parcel of the diabetic scene and will invariably occur with time, it is also widely accepted that we can do quite a bit to delay the onset. In spite of this, if renal dysfunction does occur, early diagnosis and certain specific treatments can, if not reverse, at least slow down the rate of progression of the renal dysfunction so that it reaches its end stage at a very late age.

So how are we to avoid or the least delay the onset and rate of progression of renal dysfunction?

Early diagnosis of the onset of complications is a crucial factor. However, early in the diabetic nephropathy, there are no clinical signs or symptoms of renal disease. Glomerular changes can be identified only by renal biopsy which is impractical to carry out in every patient!

From a clinical viewpoint, every patient with diabetes who presents for the first time and regularly thereafter should be tested for the presence of microalbuminuria. Aggressive intervention can delay and possibly stop progression through the stages of diabetic nephropathy. Unfortunately, many patients often seek medical attention only after having progressed to stage 3 or 4.

I do not agree with those who feel that screening for microalbuminuria is not as useful in type 2 diabetes because it is not as clearly predictive of progression to overt nephropathy as in Type 1 diabetes. As we have discussed before, due to the insiduos onset of Type 2 DM, one may not be able to see a distinct prediction of progression to end stage renal disease, but treating the raised albumin levels is definitely helpful. Moreover, the presence of microalbuminuria is associated with an increased risk of developing cardiovascular disease and retinopathy.

Even normally, a person excretes about 5 micrograms of albumin per minute in his urine. With incipient diabetic nephropathy, the amount of albumin that the patient excretes in the urine increases and this should alert us to the possibility of diabetic kidney disease.

Incipient nephropathy is the stage of microalbuminuria;

Microalbuminuria is defined as albumin excretion rate:

1. Between 30-300mg per 24 hours, or
2. An albumin excretion rate exceeding 20ug/minute and less than 200ug/minute.

Albumin excretion can be estimated through the following methods:

1. 24 hour urine collection.
2. Timed collection, say over a period of four hours.
3. Spot urinary sample

The results are analysed as follows:

Although dipsticks are available to detect microalbumin levels, they are costly. It may be worthwhile to do a spot or timed collection of urine and then see the albumin to creatinine ratio to judge the level of renal involvement.

In the absence of methods to routinely look for the presence of microalbuminuria, the use of dipsticks to look for albumin in the urine must suffice to warn of the presence of diabetic nephropathy, and it is essential that this test routinely and frequently be carried out in all patients.

Unfortunately, our routine method of detecting the presence of albumin in the urine is not very sensitive and by the time albumin can be detected even by the use of the "dipstick", the amount of albumin excreted is around 150 micrograms per minute, which is too late to diagnose microalbumin excretion levels.

It should be clear that there are numerous causes for the presence of albumin in the urine and diabetic nephropathy is only one of these. Therefore, if albumin is found in the urine of a diabetic, it should not be taken to mean that the patient has nephropathy. I usually ask my patients to repeat the test after a few days and only if this positive, then I investigate to rule out the other more common causes of albuminuria. The most frequent cause of albuminuria is any infection in the urinary tract although any generalised infection in the body can cause albuminuria. Hypertension, cardiac failure and indeed drugs used in the management of these two conditions are also known to lead to albuminuria. Even in a diabetic, one should always keep in mind that the renal involvement may be due to a non-diabetic cause. Even otherwise, a very poorly controlled diabetic may show an increased excretion of albumin in the urine without signifying diabetic nephropathy. This usually corrects itself after adequate control. Many people show a positive test after exercise and importantly, although this is not well known, drinking a large amount of water may increase the albumin excretion. Many a patient when he has to go for a test where he will need to give a urine sample, drinks a large amount of water so as to be able to give the sample without any problem, without realising that this act in itself may increase the amount of albumin in the urine. It should be mentioned that this is usually seen if something like two or three big glasses of water are rapidly drunk. It should also be remembered that many young people normally excrete albumin in the upright position.

In other words there are numerous causes of an increase in the urinary albumin excretion and all these have to be ruled out before one accepts the possibility that the albuminuria could be due to diabetic nephropathy.

Pointers to A "NON DIABETIC" cause of raised UAE

1. A more rapid decrease in the GFR than is expected.
2. Sudden development of nephrotic syndrome.
3. Absence of retinopathy.
4. Presence of hematuria; although red cell casts have been described in some patients.
5. Renal bruit.
6. Absent pedal pulses.
7. Disproportionately high serum potassium.
8. Sudden deterioration in renal function after starting ACE inhibitors.
9. Presence of cardiac failure, and the use of drugs, like diuretics, in its management.
10. Testing after heavy exercise.
11. Testing during acute illness.
12. High protein intake.
13. Decompensation of metabolic control, including recent ketosis.

Diabetic nephropathy should only be diagnosed when seen to be present on repeat testing and when other causes of raised urinary albumin have been excluded.

I feel that checking for microalbumin levels and especially repeat testing is usually not feasible in most cases. I usually start the patient on a small dose of an ACE inhibitor or an Angiotensin Receptor Blocker (ARB) or a combination of both irrespective of whether the patient has hypertension or not. There is overwhelming evidence to suggest that the use of these agents can reverse the early or incipient diabetic nephropathy or at the very least slow down significantly the progression.

Strict blood sugar control is important in the protection of kidney function.

Onset of diabetic nephropathy may be avoided with good glycemic control. Interventional and epidemiologic studies have confirmed the benefits of tight glycemic control in avoiding or delaying onset of diabetic nephropathy in patients with type 1 diabetes. In one often quoted study, the DCCT, (average HbA1c level, 7.1%), in the primary-prevention group, who had type 1 diabetes for less than 5 years and had no retinopathy, patients who received intensive versus standard insulin therapy had a 34% decrease in the frequency of microalbuminuria and no significant decrease in the frequency of macroalbuminuria. In the secondary-prevention group, who already had mild retinopathy, patients who received intensive therapy had a significant decrease in both microalbuminuria (43%) and macroalbuminuria (56%).

In patients with type 2 diabetes, a recent interventional study showed a decrease in the frequency of development of both microalbuminuria (57%) and macroalbuminuria (70%) with intensive insulin therapy. However, since type 2 diabetes is diagnosed, on average, 8 years after onset, diabetic nephropathy may have already developed in many patients.

There are some who feel that once diabetic nephropathy has set in, the importance of optimal glycemic control is little if any, in retarding the progression of the renal dysfunction. But this is far from true. Results from pancreatic transplant recipients in which true euglycemia is restored suggest otherwise. In fact, optimal glycemic control in these patients led to either an absence of albuminuria or a significant lowering of the urinary albumin excretion.

To sum up this aspect, optimal glycemic control is important in delaying the onset of diabetic nephropathy and is also important in retarding the progress of the nephropathy once it has set in.

Aggressive blood pressure control is by far the most important factor in protecting kidney function, regardless of the stage of DN. Even those who believe that there is a point of no return in so far as glycemic control is concerned agree that optimal control of the blood pressure does retard the progression of diabetic nephropathy.

The goal of treatment is:

• 120 - 130 mm Hg systolic blood pressure and
• 70 - 80 mm Hg diastolic blood pressure.

We have already referred to starting an ACE inhibitor (ACEi) or an Angiotensin Receptor Blocker (ARB) even when the patient does not have hypertesnion in order to delay the onset of nephropathy. These drugs continue to be the mainstay in optimizing the raised blood pressure, but often combination therapy with other groups of blood pressure lowering drugs are necessary. I have discussed the management of hypertesnion in a patient with diabetes in a separate chapter.

With an aggressive treatment approach, the decline in renal function can be reduced to half of the decline seen without treatment (ie, from 10% to 5% per year). Whilst this may not seem to be much, one should realize that this may mean that the patient reaches end stage renal disease state possibly 15-20 years later than he would without optimal management of the hypertension!

Aggressive treatment of dyslipidemias, surprisingly have been shown to be beneficial. Hyperlipidemia is common in diabetic patients, a tendency that is increased by the development of renal insufficiency.

In patients with type 1 diabetes, the incidence of myocardial infarction is not increased before age 35. However, after age 35, it is increased fourfold, and when proteinuria is present, it is increased by a factor of 140. The fourfold increase after age 35 could potentially be due to the presence of microalbuminuria. In patients with type 2 diabetes, diabetic nephropathy, or microalbuminuria, the incidence of myocardial infarction is also increased.

Risk factors for ischemic heart disease, which occur in the presence of albuminuria, are hypertension, increased low-density lipoprotein (LDL) cholesterol and triglyceride levels, a decreased high-density lipoprotein cholesterol level, and increased platelet aggregation and clotting factors. However, albuminuria is a significant independent risk factor. The presence of albuminuria suggests that large-vessel walls are more permeable to lipoproteins or damage from local release of growth factors, as occurs in the glomerulus.

Aggressive treatment of dyslipidemia in patients with diabetic nephropathy may have beneficial effects on not only macrovascular disease but also diabetic microvascular disease (ie, retinopathy and nephropathy). Several studies of treatment of dyslipidemia have shown improvement in retinopathy, and one double-blind study showed stabilization of renal function. Other studies have shown a positive effect of lipid lowering on other glomerular diseases.

Dietary protein restriction is minimally protective. A high-protein diet can further damage the kidneys in people with diabetic nephropathy and/or chronic renal failure (CRF). Protein restriction must be cautiously implemented because of the risk for malnutrition. In general, dietary protein intake should be limited to 0.6 to 0.8 grams per kilogram (0.02 - 0.028 oz/lb) of body weight each day.

A low-protein diet (0.6 g/kg of body weight) has the theoretical advantages of decreasing glomerular hypertension, reducing proteinuria, and slowing the decline in renal function. The efficacy of a low-protein diet in diabetic nephropathy has been questioned, but a recent meta-analysis found it to have a positive effect. Since high protein intake has the potential to accelerate the decline in renal function, at least some degree of protein restriction is indicated.

There are, however, potential problems associated with a low protein diet. In addition to difficulty with compliance due to concurrent fat and simple carbohydrate restriction, diabetics are at increased risk for protein malnutrition because the reduction in intake may be associated with enhanced protein breakdown induced by insulin deficiency. Recent experimental studies also suggest that restricting all components of protein intake may limit the potential efficacy of this regimen. The amino acid L-arginine is the precursor of the vasodilator nitric oxide (endothelium-derived relaxing factor). The administration of L-arginine to diabetic rats with nephropathy ameliorates both the glomerular hyperfiltration and the degree of proteinuria. Thus, limiting L-arginine intake as part of a protein restricted diet may not be desirable.

Maintain hydration In patients with diabetic nephropathy, avoidance of dehydration is an important factor in maintaining renal function, since a period of dehydration can cause an irreversible decline. Therefore, any acute illness that causes dehydration should be treated aggressively with intravenous fluids.

The most common cause of dehydration in patients with diabetic nephropathy is overuse of diuretics. Diuretic doses should be adjusted so patients experience nocturnal ankle edema without morning ankle edema. All patients with diabetes should be examined for physical signs of dehydration at each clinic visit.

It is absolutely essential that there should be adequate hydration. It is well known that dehydration can adversely affect the kidney. That is the reason why all diabetics should always be asked to drink an adequate amount of water so that normal quantities of urine are passed. I ask my patients to drink a glass of water at bedtime and to have some liquids on waking up. A problem that arises in our country is the fasts that people keep, especially those types of fasts where even water is not allowed. This in my opinion is harmful to some extent to a diabetic kidney, but one can only firmly advise in this matter as questions of religion are involved.

But one area where doctors can definitely do something is regarding the advise we give the patient when they have to go for their blood tests. Often the patients are asked to go fasting and are told to have nothing from 10pm the previous night. By the time the patient finishes giving the blood it often happens that more than 12 hours have elapsed without any liquid intake. I have never understood the reason for not allowing the patient to have even water. I have come across no evidence that having a glass of water in the morning would in any significant manner affect the test results! Unfortunately, this standing instructions to go completely fasting have become the "order of the day" and is accepted without question. The problem even gets worse when the patient has to go for an X-ray examination on a fasting stomach. By the time these tests are over, more than 12-14 hours may have elapsed without water. Whenever my patient is called for an X-ray in the fasting stage, I usually make it a point to inquire whether even a glass of water would affect the quality of the X-rays. If this is so, then I insist that my patient be taken up first in preference to other non-diabetics. I also instruct the patient to have more than the normal amount of water the previous night. I am not implying that one occassion that the patient stays without water for about 12 hours will cause a renal shutdown, but when there is no need to be without water and when one knows that dehydration can harm the diabetic kidney, is it not better to take all precautions to avoid even mild dehydration? If one thinks of the number of times that we ask patients to go fasting for something or the orther, and one can well imagine the these small "insults" to the kidneys may well add up! And it is so simple to avoid these insults.

Infections of the Urinary Tract must be treated adequately and the urine should be tested repeatedly and regularly for the presence of any infections which should be ruthlessly eradicated.

By itself, this may appear trivial but they may add up over the years and avoiding them may make the crucial difference between the patient who remains at a stage where there is just albuminuria as compared to reaching a stage of full blown renal failure where life can be maintained only with dialysis or renal transplant.

UTIs are detrimental to the diabetic kidney and the best solution to this is early detection and adequate management. Although such infections may be suspected from symptoms like burning micturation, dysuria, passing small but frequent urine, mild infections of the urinary tract may go unnoticed and may only be detected when the complete urine examination is done. Urinary tract infections are more common in diabetics. Besides the fact that poorly controlled diabetics, in general, have a tendency to infections, long- standing diabetics, have some degree of autonomic neuropathy which leads to bladder atony, incomplete emptying and stagnation of some urine. This coupled with the presence of glucose in the urine of poorly controlled diabetics favors the growth of bacteria and infection. The stagnation of the urine also makes it that much more difficult to eradicate any infection.

I usually ask my patients, especially women who are more prone to chronic urinary tract infections, to have a complete urine examination done every three months or so irrespective of whether these have any signs and symptoms of urinary infection or not. If there is any evidence of infection, then I ask for a culture and sensitivity and treat the infection until the urine is sterile. In patients who are prone to recurrent urinary infections, the antibiotic to which the organism is sensitive may be continued in a small nighttime dose for a prolonged period. This often helps in avoiding frequent infections. The patient may also need to be taught methods which will help in a more complete emptying of the bladder. Occassionally drugs may be of some aid and in very severe case surgery may be required especially in male patients who may have some degree of an enlarged prostate that makes complete emptying of the bladder difficult.

Smoking worsens hypertension and albuminuria by increasing catecholamine levels in patients with diabetes without autonomic neuropathy. Therefore, smoking cessation is imperative.

Avoid renal damage from drug use. Some drugs should be avoided completely in patients with nephropathy whilst the dose of some other drugs needs to be carefully adjusted depending on the state of the renal function. It would be worthwhile to avoid the use of these drugs in cases with diabetic nephropathy especially if safer alternatives are available. Here again one may feel that occassionally taking a drug with a potential for renal toxicity may not have a significant effect on the final outcome of the renal disease, but these "minor" matters do add up and if one can avoid taking even these-minor risks, I really cannot find a valid reason for not doing so.

One area where I would like to draw special attention is the use of radio-contrast media in investigations. Whenever possible, radiocontrast material should be avoided, since patients with diabetic nephropathy are at increased risk of radiocontrast-induced renal shutdown. Additional major risk factors for radiocontrast-induced renal shutdown are sepsis, dehydration, use of nephrotoxic antibiotics, use of antifungal agents or nonsteroidal anti-inflammatory drugs, and the presence of cardiac or pulmonary disease or other causes of hypoxia. However, the most predictive factor is the volume of iodinated radiocontrast material used. The risk of renal shutdown is minimal with intravenous urography or computed tomography of the head and greatest with coronary angiography. Coronary angiography is often considered in patients with diabetic nephropathy because their incidence of ischemic heart disease is increased; however, it should be performed only when absolutely necessary and with the lowest possible radiocontrast dose.

Renal Replacement Therapy. Once patients with DN progress to stage 5 (end-stage renal disease, ESRD), renal replacement therapy (RRT) is implemented. The RRT options for DN patients include the following:

• Hemodialysis, removal of the blood's waste products through filtration outside of the body
• Peritoneal dialysis, filtration through the membrane lining the abdominal cavity; fluid is instilled into the peritoneal space, and then drained
• Kidney transplantation