Diabetic nephropathy (kidney disease) is the leading cause of kidney failure in the United States. That’s the bad news. The good news is that the outlook for protecting your kidneys has gotten much brighter over the past decade or so. There are now a number of measures you can take that have been scientifically proven to protect your kidneys and lower the risk of developing diabetes-related kidney disease. Here’s what the research shows.
When good kidneys go bad
Your kidneys, which are each about the size of your fist, are located near the middle of your back, just below the rib cage. By no coincidence, they are shaped like kidney beans. One of their jobs is to filter waste products and extra water from the bloodstream. This waste and excess water, in the form of urine, flow through tubes called ureters and into the bladder. The bladder stores urine until it is full enough to create the urge to urinate.
How does this filtering process work? Each kidney is made up of about one million tiny filtering units called nephrons. Tiny blood vessels called arterioles deliver blood to the nephrons. Within each nephron, the blood vessels form a complex called a glomerulus. It is within these glomeruli that the filtering activity actually takes place. The filtered blood leaves through another arteriole and is eventually carried back to the heart. Meanwhile, the material filtered from the blood passes through a tubule, where it is converted to urine, and then carried to the bladder through the ureters. (See “The Function of a Kidney” for more information about kidney anatomy.)
Diabetes sets the stage for kidney damage. Chronic high blood glucose levels, often in combination with high blood pressure, damage the glomeruli and progressively diminish kidney function. (High blood pressure alone is the second-leading cause of kidney failure behind diabetes.) This type of kidney dysfunction is known as diabetic nephropathy. In its earliest stages, it has no symptoms; however, the “silent” damage going on behind the scenes can still pave the way for kidney failure.
In the first stage of diabetic nephropathy, called hyperfiltration, the kidneys filter larger quantities of blood than usual in an attempt to compensate for damaged nephrons. Hyperfiltration is the first stage of the problem, but it does not necessarily lead to kidney failure. In fact, some people may stay in this stage and not progress further, especially if they maintain control of their blood glucose and blood pressure levels.
If damage from high blood glucose levels (and high blood pressure) continues for many years, this may lead to the second stage, called microalbuminuria. Normally, the kidneys do not allow significant amounts of proteins from the bloodstream into the urine. However, once they become damaged, tiny amounts of protein leak into the urine. The appearance of small amounts of the protein albumin in the urine indicates the start of diabetic nephropathy. (Albumin in the urine can also signal the possibility of glomerular disease or chronic high blood pressure, while the presence of other types of protein would raise suspicions of other types of kidney disease.) Laboratory tests can detect this small amount of albumin while kidney disease is still fairly treatable. However, your doctor must specifically request a microalbumin test of your urine, because standard urine tests are not sensitive enough to notice these small amounts of albumin.
As in hyperfiltration, some people may develop microalbuminuria but not progress to later stages of kidney disease, especially if it is caught and treated early. However, even if nephropathy does not develop, the presence of microalbuminuria is itself a risk factor for cardiovascular diseases in people with Type 2 diabetes.
In the third stage (sometimes called overt diabetic nephropathy or nephrotic syndrome), large amounts of albumin spill into the urine (a condition called macroalbuminuria), which can be detected even on routine urine tests. As more albumin passes into the urine, less remains in the bloodstream. Since these proteins normally help to retain fluid in the bloodstream, their loss allows fluid to begin leaking out of the arteries and capillaries. This fluid tends to build up in the tissues, a condition known as edema. Excess fluid can collect in the legs and feet and later even in the chest (pleural effusion), around the heart (pericardial effusion), and in the abdomen (ascites), causing symptoms such as fatigue, chest pain, and shortness of breath. Also at this stage, people tend to develop high blood pressure if they do not have it already (people who already have high blood pressure will find it worsens).
In the fourth stage, called advanced clinical nephropathy, the kidneys can no longer remove most of the body’s waste products. Toxins begin to build up in the bloodstream, and anemia (low red blood cell count) may develop, causing fatigue.
In the fifth stage, called kidney failure, the kidneys barely function at all, causing uremia, the buildup of urea and other waste products in the blood. Uremia causes symptoms such as nausea, vomiting, and fatigue. In 50% of people who have Type 1 diabetes and overt nephropathy, kidney failure develops within 10 years. Among people with Type 2 diabetes and overt nephropathy, 20% progress to kidney failure in 20 years. People with kidney failure require dialysis, a treatment that takes over the function of the kidneys by filtering waste products and removing water from the blood. In some cases, people with kidney failure can get a kidney transplant, but most must wait for a long time for a suitable donor kidney to become available.
If you work with a nephrologist (a physician who specializes in kidney diseases) to treat problems with diabetic nephropathy, he may refer to different stages than the ones described here because the National Kidney Foundation (NKF) has its own five-stage classification system for chronic kidney disease. The NKF bases its system on kidney filtering function alone, so it does not differentiate between the initial causes of the kidney disease. In the NKF’s model, people with diabetic nephropathy who show microalbuminuria would usually be grouped in “stage 1 chronic kidney disease.” Kidney failure occurs in “stage 5 chronic kidney disease.”
One of the best screening tools for the earliest stages of diabetic kidney disease is the urine microalbumin test, which can be done in one of three ways and also involves a check of urinary creatinine levels. (Creatinine is a by-product of normal muscle breakdown.) To monitor your albumin levels, your health-care team can order a one-time in-office check of urine (a “random spot collection,” often done first thing in the morning), a 24-hour urine collection (analyzing all the urine you produce in 24 hours), or a timed collection (analyzing all the urine you produce over a certain number of hours). The 24-hour sample is supposed to give the most accurate results (and may still be recommended for certain people with unusual protein intakes or extreme muscle loss), but because it can be a hassle and because the shorter tests offer good accuracy when corrected by checking creatinine levels, many health-care providers simply use the shorter tests. (Several companies sell home test kits that allow people to mail urine samples to a laboratory for microalbumin testing; however, you should discuss this option with your health-care team before trying one.)
If a test shows the presence of albumin in the urine, the physician usually orders one or two repeat tests to confirm the result (because albumin levels in urine can vary from day to day). To reach a firm diagnosis of microalbuminuria, a person needs to have certain levels of albumin in the urine on at least two of three tests in three to six months. The more albumin that is in the urine, the more severe the kidney disease.
Currently, the American Diabetes Association (ADA) recommends starting to screen for microalbuminuria in people who have had Type 1 diabetes for 5 years and at the time of diagnosis in people with Type 2 diabetes (since diabetes may have been developing and causing problems for many years before diagnosis). All people with diabetes should be screened annually after their first microalbumin test (or have repeat testing within six months if a test result is positive for microalbuminuria).
While microalbuminuria may be a very sensitive test in people with Type 1 diabetes, there is evidence that testing for microalbuminuria alone may miss many cases of diabetic kidney disease in people with Type 2 diabetes. In a study reported in the June 25, 2003, issue of The Journal of the American Medical Association, researchers studied data from 1,197 people with Type 2 diabetes who were 40 years or older. In addition to testing for microalbuminuria, they tested participants’ glomerular filtration rate (GFR), a measure of how well the kidneys are able to filter waste from the blood. GFR is considered the best gauge of kidney function (and is the measure the NKF uses to divide up its five-stage kidney disease classification system), and a persistently low GFR indicates kidney disease. Of those study subjects who had a low GFR, 55% did not have microalbuminuria. So some medical experts now recommend that people with Type 2 diabetes also have their GFR tested annually to catch early nephropathy that a microalbumin test may miss.
GFR cannot be measured directly. Currently, it is closely approximated, in part, by using the blood concentration of creatinine. Healthy kidneys excrete creatinine in the urine, so a buildup of creatinine in the blood shows that the kidneys aren’t working well. By measuring the concentration of creatinine in the bloodstream and using it in an equation that takes into account the person’s weight, age, sex, and race, doctors can estimate the GFR and get a sense of kidney function. The higher the blood creatinine level, the lower the GFR. Some physicians also use the blood creatinine level and GFR calculation to track the decline of kidney function and to gauge any benefits of treatment.
Prevention and treatment
At least two large studies have shown beyond a shadow of a doubt that tight blood glucose control can significantly lower the risk of developing microalbuminuria and diabetic kidney disease. The glycosylated hemoglobin (HbA1c) test gives a measure of one’s long-term control of blood glucose and hence one’s risk for diabetic complications. The ADA currently recommends that people with diabetes have an HbA1c test two to four times each year and strive for an HbA1c level under 7%.
Controlling blood pressure is important not only for reducing the risk of cardiovascular disease but also for protecting the kidneys. According to the ADA, both high systolic blood pressure (the pressure at the moment of the heart beat) and high diastolic pressure (the pressure between beats) can speed up the progression of diabetic kidney disease, and aggressive treatment of high blood pressure can greatly decrease the rate of fall in GFR. Treating high blood pressure has also been shown to raise life expectancy and reduce the need for dialysis and transplantation once diabetic kidney disease has developed. According to the ADA, people with diabetes should strive to maintain a systolic blood pressure under 140 mm Hg and a diastolic pressure under 80 mm Hg.
In some cases, initial therapy for high blood pressure should consist of lifestyle modifications, such as losing weight, cutting back on sodium and alcohol consumption, and getting more exercise. One of the most effective lifestyle changes would be to follow the DASH (Dietary Approaches to Stop Hypertension) eating plan, which is a diet low in saturated fat, total fat, and cholesterol that emphasizes fruits, vegetables, and low-fat dairy products. The DASH diet is most effective when combined with a reduction in sodium intake. You can download a copy of “Facts About the DASH Eating Plan” that includes a week’s worth of menus from www.nhlbi.nih.gov/health/public/heart/hbp/dash or call (301) 592-8573 for a free copy.
For treating high blood pressure in people with diabetes — or for treating anyone with diabetes and microalbuminuria or overt nephropathy — specific blood-pressure-lowering drugs called angiotensin-converting enzyme (ACE) inhibitors and angiotensin- II receptor blockers (ARBs) are the drugs of choice. ACE inhibitors include quinapril (Accupril), perindopril (Aceon), ramipril (Altace), captopril (Capoten), benazepril (Lotensin), trandolapril (Mavik), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipriol (Univasc), and enalapril (Vasotec). ARBs include candesartan (Atacand), irbesartan (Avapro), olmesartan (Benicar), losartan (Cozaar), valsartan (Diovan), telmisartan (Micardis), and eprosartan (Teveten). These drugs appear to have a protective effect on kidneys above and beyond blood pressure control.
ACE normally converts a hormone called angiotensin I to a related hormone called angiotensin II, which constricts blood vessels, increases sodium and water retention, activates the sympathetic nervous system, stimulates fibrosis (stiffening) of the heart and blood vessels, and promotes heart cell growth. The immediate net effect of these changes is to raise blood pressure, but over time this hormone can cause damage to the heart and kidneys. ACE inhibitors block the action of ACE, thus decreasing the amount of angiotensin II and in turn minimizing its effects.
ARBs also work to decrease the effects of angiotensin II, but at a different point in the process. For angiotensin II to exert its effects throughout the body, it must bind to certain receptors (much as a key fits into a lock) on cell surfaces. ARBs prevent angiotensin II from binding to its receptors and thus reduce its effects.
Large numbers of studies have shown that in people with diabetes, ACE inhibitors can have a number of beneficial effects, including preventing or delaying the progression of nephropathy in people with microalbuminuria or overt diabetic nephropathy, decreasing the risk of heart attack and stroke, and decreasing mortality, so people with diabetes and hypertension are routinely prescribed ACE inhibitors.
Like ACE inhibitors, ARBs decrease levels of albumin in the urine and have been shown to effectively prevent progression of nephropathy in people with microalbuminuria or overt diabetic nephropathy. If an ACE inhibitor or ARB used alone is not sufficient to lower blood pressure, other blood-pressure-lowering drugs such as diuretics may need to be added; ACE inhibitors and ARBs can even be used together. (Read “Analgesics and Kidney Health” for information on how various over-the-counter medicines affect the kidneys.)
The effectiveness of dietary protein restriction in protecting the kidneys remains somewhat controversial. Dietary protein restriction has been shown to slow the progression of kidney disease in some animal models. Small clinical studies in people with diabetic kidney disease have shown that people who were able to restrict their dietary protein to 0.8 grams per kilogram of body weight per day (which is actually also the Recommended Dietary Allowance of protein for adults) were able to modestly slow the rate of fall in GFR. That level of protein consumption works out to about 54 grams of protein per day for a person weighing 150 pounds.
In a study reported in the March 18, 2003, issue of Annals of Internal Medicine, researchers studied dietary protein and kidney function in women with either normal kidney function or mild kidney disease. Female nurses, 42–68 years old, reported on their eating habits over a period of 11 years, after which their GFR was measured. In women with normal kidney function at the start of the study, there was no association between protein intake and GFR. Yet, in women with mild kidney disease at the start of the study, GFR declined as they ate more protein — especially nondairy animal protein. Experts now recommend a protein intake of 0.8 grams per kilogram of body weight per day in people who have overt nephropathy — and perhaps lower if this has a beneficial effect on the GFR. Protein-restricted diets should be designed by a registered dietitian, who can take into consideration all aspects of nutrition and dietary management of diabetes.
Risk reduction steps
Diabetic nephropathy is the leading cause of kidney failure in the United States. Yet with proper screening and diagnosis, some lifestyle changes, and good control of blood glucose and blood pressure with appropriate medicines, you can greatly reduce your chances of developing advanced kidney disease. The other good news: These same measures can also protect your heart, blood vessels, eyes, and nerves.