Kidney disease of diabetes.

Each year in the United States, nearly 80,000 people are diagnosed with kidney failure, a serious condition in which the kidneys fail to rid the body of wastes. Kidney failure is the final stage of a slow deterioration of the kidneys, a process known as nephropathy.

Diabetes is the most common cause of kidney failure, accounting for more than 40 percent of new cases. Even when drugs and diet are able to control diabetes, the disease can lead to nephropathy and kidney failure. Most people with diabetes do not develop nephropathy that is severe enough to cause kidney failure. About 16 million people in the United States have diabetes, and about 100,000 people have kidney failure as a result of diabetes.

People with kidney failure undergo either dialysis, which substitutes for some of the filtering functions of the kidneys, or transplantation to receive a healthy donor kidney. Most U.S. citizens who develop kidney failure are eligible for federally funded care. In 1997, the Federal Government spent about $11.8 billion on care for patients with kidney failure.

African Americans, American Indians, and Hispanic Americans develop diabetes, nephropathy, and kidney failure at rates higher than average. Scientists have not been able to explain these higher rates.

Nor can they explain fully the interplay of factors leading to diabetic nephropathy--factors including heredity, diet, and other medical conditions, such as high blood pressure. They have found that high blood pressure and high levels of blood sugar increase the risk that a person with diabetes will progress to kidney failure.

Two Types of Diabetes

There are two types of diabetes mellitus. In patients with either type, the body does not properly process and use certain foods. The human body normally converts carbohydrates to glucose, the simple sugar that is the main source of energy for the body's cells. To enter cells, glucose needs the help of insulin, a hormone produced by the pancreas. When a person does not make enough insulin, or the body does not respond to the insulin that is present, the body cannot process glucose, and it builds up in the bloodstream. High levels of glucose in the blood or urine lead to a diagnosis of diabetes. Both types of diabetes can lead to kidney disease.

Type 1 Diabetes

Only about 1 in 20 people with diabetes has type 1 diabetes, which tends to occur in young adults and children. Type 1 used to be known as insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes. In type 1 diabetes, the body produces little or no insulin. People with type 1 diabetes must receive daily insulin injections. Type 1 diabetes is more likely to lead to kidney failure. About 40 percent of people with type 1 develop severe nephropathy and kidney failure by the age of 50. Some develop kidney failure before the age of 30.

Type 2 Diabetes

About 95 percent of people with diabetes have type 2 diabetes, once known as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. Many people with type 2 diabetes do not respond normally to their own or to injected insulin--a condition called insulin resistance. Type 2 diabetes occurs more often in people over the age of 40, and many people with type 2 are overweight. Many also are not aware that they have the disease. Some people with type 2 control their blood glucose with meal planning and physical activity. Others must take pills that stimulate production of insulin, reduce insulin resistance, decrease the liver's output of glucose, or slow absorption of carbohydrate from the gastrointestinal tract. Still others require injections of insulin. Between 1993 and 1997, more than 100,000 people in the United States were treated for kidney failure caused by type 2 diabetes.

The Course of Kidney Disease

The deterioration that characterizes kidney disease of diabetes takes place in and around the glomeruli, the blood-filtering units of the kidneys. Early in the disease, the filtering efficiency diminishes, and important proteins in the blood are lost in the urine. Medical professionals gauge the presence and extent of early kidney disease by measuring protein in the urine. Later in the disease, the kidneys lose their ability to remove waste products, such as creatinine and urea, from the blood. Measuring these waste products in the blood gives an indication of how far kidney disease has progressed.

Symptoms related to kidney failure usually occur only in late stages of the disease, when kidney function has diminished to less than 10 to 25 percent of normal capacity. For many years before that point, kidney disease of diabetes is a silent process.

Five Stages

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

Stage I

The flow of blood through the kidneys, and therefore through the glomeruli, increases-this--is 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. In its earliest stages, microalbuminuria may not be detected on each evaluation. But as the rate of 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.) A special test is required to detect microalbuminuria. 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. Because such tests often involve dipping indicator strips into the urine, they are referred to as "dipstick methods." Stage III sometimes is referred to as "dipstick-positive proteinuria" (or "clinical albuminuria" or "overt diabetic nephropathy"). Some patients develop high blood pressure. The glomeruli suffer increased damage. 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 to 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. Type 1 diabetes accounts for only 5 to 10 percent of all diagnosed cases of diabetes, but type 1 accounts for 30 percent of the cases of kidney failure caused by diabetes.

Effects of High Blood Pressure

High blood pressure, or hypertension, is a major factor in the development of kidney problems in people with diabetes. Both a family history of hypertension and the presence of hypertension appear to increase the chances of developing kidney disease. Hypertension also accelerates the progress of kidney disease where it already exists.

In the past, hypertension was defined as blood pressure exceeding 140 millimeters of mercury-systolic and 90 millimeters of mercury-diastolic. Professionals shorten the name of this limit to 140/90 or "140 over 90." The terms systolic and diastolic refer to pressure in the arteries during contraction of the heart (systolic) and between heartbeats (diastolic).

In 1997, the National Heart, Lung, and Blood Institute issued new blood pressure goals specifically for people with diabetes and people with renal insufficiency in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). In JNC VI, the committee recommends that people with diabetes keep their blood pressure at 130/85 or lower and that people with renal insufficiency (proteinuria greater than 1 gm/24 hrs) keep their blood pressure at 125/75 or lower.

Hypertension can be seen not only as a cause of kidney disease, but also as a result of damage created by the disease. As kidney disease proceeds, physical changes in the kidneys lead to increased blood pressure. Therefore, a dangerous spiral, involving rising blood pressure and factors that raise blood pressure, occurs. Early detection and treatment of even mild hypertension are essential for people with diabetes.

Preventing and Slowing Kidney Disease

Blood Pressure Medicines

Scientists have made great progress in developing methods that slow the onset and progression of kidney disease in people with diabetes. Drugs used to lower blood pressure (antihypertensive drugs) can slow the progression of kidney disease significantly. One kind of drug, angiotensin-converting enzyme (ACE) inhibitors, has proven to be effective in preventing progression to stages IV and V. (1) Diuretics, beta-blockers, adrenergic nervous system modulators, and calcium channel blockers also may enhance blood pressure control in patients with diabetes mellitus.

An example of an effective ACE inhibitor is captopril, which doctors commonly prescribe for treating kidney disease of diabetes. The benefits of captopril extend beyond its ability to lower blood pressure: it may directly protect the kidney's glomeruli. ACE inhibitors have lowered proteinuria and slowed deterioration even in patients with diabetes who did not have high blood pressure.

Any medicine that helps patients achieve a blood pressure target of 125/75 or lower provides benefits. Patients with even mild hypertension or persistent microalbuminuria should consult a physician about the use of antihypertensive medicines.

Low-Protein Diets

A diet containing reduced amounts of protein may benefit people with kidney disease of diabetes. In people with diabetes, excessive consumption of protein may be harmful. Experts recommend that most patients with stage III or stage IV nephropathy consume limited amounts of protein.

Intensive Management of Blood Glucose

Antihypertensive drugs and low-protein diets can slow kidney disease when significant nephropathy is present, as in stages III and IV. A third treatment, known as intensive management of blood glucose or glycemic control, has shown great promise for people with type 1 and type 2 diabetes, especially for those in early stages of nephropathy.

Intensive management is a treatment regimen that aims to keep blood glucose levels close to normal. The regimen includes frequently testing blood glucose, administering insulin frequently throughout the day on the basis of food intake and exercise, following a diet and exercise plan, and frequently consulting a health care team. Some people use an insulin pump to supply insulin throughout the day.

A number of studies have pointed to the beneficial effects of intensive management. Two such studies, funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, are the Diabetes Control and Complications Trial (DCCT) (2) and a trial led by researchers at the University of Minnesota Medical School. (3) A third study, conducted in the United Kingdom, is the U.K. Prospective Diabetes Study (UKPDS). (4)

The DCCT, conducted from 1983 to 1993, involved 1,441 participants who had type 1 diabetes. Researchers found a 50 percent decrease in both development and progression of early diabetic kidney disease (stages I and II) in participants who followed an intensive regimen for controlling blood glucose levels. The intensively managed patients had average blood glucose levels of 150 milligrams per deciliter--about 80 milligrams per deciliter lower than the levels observed in the conventionally managed patients.

In the Minnesota Medical School trial, researchers examined kidney tissues of people with long-standing diabetes who received healthy kidney transplants. After 5 years, patients who followed an intensive regimen developed significantly fewer lesions in their glomeruli than patients not following an intensive regimen. This result, along with findings of the DCCT and studies performed in Scandinavia, suggests that any program resulting in sustained lowering of blood glucose levels will be beneficial to patients in the early stages of diabetic nephropathy.

The UKPDS--a 20-year trial conducted in England, Ireland, and Scotland--tested the effects of intensive blood glucose and blood pressure control in people with type 2 diabetes and found similar benefits for this group.

Dialysis and Transplantation

When people with diabetes experience kidney failure, they must undergo either dialysis or a kidney transplant. As recently as the 1970s, medical experts commonly excluded people with diabetes from dialysis and transplantation, in part because the experts felt the damage caused by diabetes would offset the benefits of the treatments. Today, because of better control of diabetes and improved rates of survival following treatment, doctors do not hesitate to offer dialysis and kidney transplantation to people with diabetes.

Currently, the survival of kidneys transplanted into patients with diabetes is about the same as survival of transplants in people without diabetes. Dialysis for people with diabetes also works well in the short run. Even so, people with diabetes who receive transplants or dialysis experience higher morbidity and mortality because of coexisting complications of the diabetes--such as damage to the heart, eyes, and nerves.

Looking to the Future

The incidences of both diabetes and kidney failure caused by diabetes have been rising. Some experts predict that diabetes soon might account for half the cases of kidney failure. In light of the increasing morbidity and mortality related to diabetes and kidney failure, patients, researchers, and health care professionals will continue to benefit by addressing the relationship between the two diseases. NIDDK is a leader in supporting research in this area.

Several areas of research supported by NIDDK hold great potential. Discovery of ways to predict who will develop kidney disease may lead to greater prevention, as people with diabetes who learn they are at risk institute strategies such as intensive management and blood pressure control. Discovery of better anti-rejection drugs will improve the results of kidney transplantation in patients with diabetes who develop kidney failure. For some people with type 1 diabetes, advances in transplantation--especially transplantation of insulin-producing cells of the pancreas could lead to a cure for both diabetes and the kidney disease of diabetes. (5)

Primary Diagnoses (Causes)
for Kidney Failure (1998)

Polycystic Kidney Disease   2.9%

Other Causes               18.6%

Diabetes                   43.2%

High Blood Pressure        23%

Glomerulonephritis         12.3%

Note: Table made from pie chart.

Good Care Makes a Difference

If you have diabetes:

* Have your doctor measure your hemoglobin A-1-c level at least twice a year. The test provides a weighted average of your blood glucose level for the previous 3 months. Aim to keep it at less than 7 percent.

* Work with your doctor regarding insulin injections, medicines, meal planning, exercise, and blood glucose monitoring.

* Have your blood pressure checked several times a year. If blood pressure is high, follow your doctor's plan for keeping it near normal levels. Aim to keep it at less than 130/85. If you have proteinuria, aim to keep your blood pressure at less than 125/75.

* Ask your doctor whether you might benefit from an ACE inhibitor.

* Have your urine checked yearly for microalbumin and protein. If there is protein in your urine, have your blood checked for elevated amounts of waste products such as creatinine.

* Ask your doctor whether you should reduce the amount of protein in your diet. Ask for a referral to see a registered dietitian to help you with meal planning.

References

(1.) Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. New England Journal of Medicine. 1993;329(20):1456-1462.

(2.) National Diabetes Information Clearinghouse. Diabetes Control and Complications Trial. Washington, DC: U.S. Government Printing Office; 1994. NIH publication 97-3874. Fact sheet.

(3.) Barbosa J, Steffes MW, Sutherland DE, Connett JE, Rao KV, Mauer SM. Effect of glycemic control on early diabetic renal lesions. Journal of the American Medical Association. 1994;272(8):600-606.

(4.) UKPDS 38. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. British Medical Journal. 1998; 317:703-713.

(5.) Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. New England Journal of Medicine. 1998;332(2):69-75.