Reversing kidney disease in diabetes


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Posted by JoeC on 23:54:53 2006/02/15


An interview with Bruce Perkins, M.D., M.P.H., F.R.C.P.C.
Reversing kidney disease in diabetes
Tight control of blood sugar and cholesterol can help prevent--and possibly reverse--the ravages of diabetes.
Published: January/February 2004

For the thousands of Americans living with type 1 diabetes, new research helps shatter a commonly held notion that elevated protein levels in the urine signal the first step in the inexorable decline in kidney function, ultimately leading to kidney failure.

In a study of 386 patients with type I diabetes, individuals with microalbuminuria--leakage of small amounts of proteins from the blood into the urine--who obtained early diagnosis through frequent screening and maintained very good levels of blood sugar, blood pressure, and cholesterol actually promoted the healing process and in some cases reversed kidney complications. The six-year study, recently published in the New England Journal of Medicine, once again underscores the critical importance of early detection and aggressive intervention in preventing complications of the disease. Emerging studies continue to shed light on important risk factors that may slow and, in some cases, reverse the process by repairing initial damage to the kidneys due to diabetes.

To learn more about the study and lifestyle measures that individuals with diabetes can take to reduce the risk of kidney disease, the Post spoke with one of the paper's lead authors, Bruce Perkins, M.D., M.P.H., F.R.C.P.C., assistant professor of medicine at University of Toronto.

Post: Could you discuss the toll that diabetes can exact on kidney function?

Perkins: The effect that diabetes has on the kidneys is a major public health issue. One in three patients with type I diabetes develops end-stage kidney failure, which eventually requires either a kidney transplant or hemodialysis treatment for life. These treatments have a dramatic impact on the quality of life of patients and on the economics of care delivery.

The key to intervention is prevention. In a major finding over 15 years ago, researchers noted that when microalbuminuria develops, it is the most important predictor for the risk of progressing to kidney disease in patients with diabetes. It has become a very crucial measure in the care of patients; as a result of that research, it is recommended that all patients with diabetes be screened on a yearly basis for microalbuminuria by providing at least one urine sample to their diabetes care doctor. Until now, when microalbuminuria was diagnosed, it was believed that one could only hope to postpone--but not prevent--kidney disease by intensified efforts to control blood sugar and treatment with certain blood pressure drugs. To determine if these initial studies overestimated the risk, we investigated the finding at the Joslin Diabetes Center. The principal investigator of this study, Andrzej Krolewski, M.D., Ph.D., head of the section on genetics and epidemiology at Joslin, designed a very large clinical study to look at patients with type 1 diabetes who develop microalbuminuria to learn how their disease progresses and to determine the important risk factors for developing kidney disease. His research group has been following these patients since 1991.

Under the hypothesis that there are unique mechanisms that the body possesses to repair injury to the kidneys caused by diabetes, we studied whether it is possible, under certain conditions, to reverse microalbuminuria. Recognizing these "salutary" factors that lead to kidney repair would greatly aid in developing better clinical strategies for preventing diabetes complications.

Post: Could you tell us about the major findings of the study, which was published in the NEJM?

Perkins: First, in the earliest stages of kidney disease caused by type 1 diabetes, we found that kidney injury is still a dynamic process that can either get worse or get better--even revert back to normal. In fact, the leakage of protein subsided in 58 percent of the patients we studied, even among those who were not taking ACE inhibitors, a type of drug known to be helpful in people with microalbuminuria. This was a very surprising finding; the initial studies suggested that microalbuminuria represented a commitment to progressive kidney disease.

Second, we found that an early diagnosis of microalbuminuria by frequent screening and very good levels of blood sugar, blood pressure, and cholesterol were strong factors associated with the healing process. Although high cholesterol was known to be bad for patients with advanced kidney disease, it was not known that very low levels of cholesterol are good in the earliest stages of the disease.

Since microalbuminuria can go away and certain factors are associated with its remission, we infer that specific mechanisms of repair exist in the kidney that enable the kidney to repair itself in the early stages. When we understand these mechanisms better, we can develop more effective treatments for preventing serious kidney disease.

Post: Prior to the study, did experts believe that diabetic nephropathy was inevitable after onset of microalbuminuria?

Perkins: Yes. Microalbuminuria was felt to be the first step in an inexorable process that led to kidney failure. Once this process began, it was believed that the process could only be slowed, but not stopped. However, it was noted that people with better blood glucose control progressed more slowly to kidney disease. And in the mid-to-late '90s, clinical practice guidelines recommended that anyone with microalbuminuria receive a blood pressure medication called an ACE inhibitor to help slow the progression of the disease.

Post: Have physicians followed those guidelines?

Perkins: Many people who should be on ACE inhibitor medications are not, despite the fact that clinical trials have strongly suggested how important ACE inhibitors are in slowing the progression of disease. Whether the medicine is not prescribed or patients do not adhere to the recommendation of their doctors is unclear. In our study, about 80 percent of people are taking ACE inhibitors, but it took several years for this rate of adherence to happen.

I'd like to stress that in our research, we found that ACE inhibitors did not increase the likelihood of reversal of microalbuminuria, which was surprising. In reality, these medications probably help to counteract mechanisms of injury to the kidney, but it appears that they probably do not promote the mechanisms of repair. We therefore do not feel that doctors should rely so heavily on ACE inhibitor medications alone to prevent the advanced kidney complications from diabetes in their patients, but instead urge that a multi-factorial approach that involves very careful management of blood sugar, blood pressure, and possibly cholesterol be pursued. In the final analysis, rates of kidney disease are increasing in the American population with diabetes, despite the introduction of ACE inhibitors in the 1990s.

Post: At what point in the disease does microalbuminuria typically surface in patients with type I diabetes?

Perkins: The initial injury, marked by microalbuminuria, can appear as early as seven years after diagnosis in patients with type 1 diabetes. About half the people with type 1 diabetes will eventually develop microalbuminuria in their lifetime.

Post: Does this also apply to patients with type 2 diabetes?

Perkins: Microalbuminuria is often present at the time of type 2 diabetes diagnosis, making the need for early intervention even more pressing for this group of patients. Whether reversal of microalbuminuria occurs at similar rates as the people we have studied with type 1 diabetes, or whether the same "salutary" factors associated with this reversal applies to patients with type 2 diabetes, is not known. This has not been studied as extensively in the type 2 diabetes population, and one of our goals is to pursue that research. However, I should note that the findings of research relating to kidney disease in type I diabetes have generally applied to type 2 diabetes as well.

Post: The general recommended preventive measures for better control of diabetes include lowering blood pressure, good blood sugar control, low cholesterol, and low triglycerides. Does this study in a way reinforce previous recommendations?

Perkins: All of these measures do fall within the general care recommendations for people with diabetes, but not to the degree that our study findings suggest are necessary. Specifically, to induce reversal of microalbuminuria, we are talking about achieving very low levels of cholesterol and blood pressure.

Cholesterol, for example, is monitored in patients with diabetes in order to prevent heart disease. When cholesterol reaches a certain threshold, it is very important that patients receive dietary and lifestyle counseling to help control the levels, and often this requires the use of medications. The current study, however, suggests that people who would ordinarily be considered to have normal cholesterol levels when it comes to preventing heart disease might benefit from even lower levels if they develop microalbuminuria. This information regarding cholesterol and early kidney disease is new information.

It is important to test the effect of lowering cholesterol in people with microalbuminuria, even if their levels are in the range that we currently consider normal, to determine if they could reverse early kidney damage and be at lower risk of developing advanced kidney disease later in life. Furthermore, although we have learned that cholesterol plays a role in the repair mechanism, more research is needed to understand the exact mechanism that, in turn, may provide us with insight into a new therapy or a new approach to preventing kidney disease.

Post: Does the study provide new hope for what was previously considered a hopeless situation?

Perkins: Yes. People with type 1 diabetes who develop microalbuminuria are, in general, younger healthy people who are living life very well. When diagnosed with microalbuminuria, individuals have learned that they are at high risk of eventually needing hemodialysis or a kidney transplant. I hope that the information from this new study will empower people with diabetes to be more active in managing their condition and to work at preventing complications. After all, the reason that I do research in this area is because my goal is to see people with diabetes live their lives in an exciting, adventurous way, exactly as they would in a parallel life without diabetes. For this to occur, it is necessary for researchers, physicians, and patients to work at preventing the complications of diabetes.

Post: Does your research underscore the need for more frequent screening?

Perkins: Yes. The current recommendation is to screen a urine sample on a yearly basis: if this test is abnormal, it should be repeated twice, and microalbuminuria is diagnosed if two out of three tests are abnormal. It seems that patients and physicians do not expedite this process quickly, or they may not worry as much if the results are only slightly abnormal. We have found in our research that early, rapid diagnosis with the early initiation of therapy greatly benefits patients, even if the leakage of protein is only slightly abnormal.

Post: Once the disease is diagnosed, what is the basic treatment plan?

Perkins: Optimize blood glucose control, treat high blood pressure if present, and start an ACE inhibitor medication. Possibly one day, if our suspicions about cholesterol hold true in a clinical trial, treatment may also involve strategies for lowering cholesterol.

Post: We recently drew attention to a study published in JAMA by Dr. Holly Kramer of Loyola University. The study focused on the importance of calculating the glomerular filtration rate (GFR) and the need to better monitor the measurement. Are both measurements important but at different points in the disease?

Perkins: Yes, both of these measurements are very important. In people with diabetes, the leakage of protein in the urine occurs many years before the glomerular filtration rate, a more direct measure of kidney function, begins to decline. Currently, GFR is monitored closely at this stage for further decline in order to determine when a patient may need to begin therapy with hemodialysis or undergo a kidney transplant. Dr. Kramer's group is interested in identifying other causes of kidney disease in people with diabetes. Regardless of cause, I believe that it is very important to have an easy and accurate way to measure GFR, even in the very early stages of kidney disease. The behavior of GFR early in the course of kidney disease is an area that we are actively studying in our Joslin Diabetes Center population.

Post: Does proteinuria represent a much more advanced stage of disease?

Perkins: Yes. Kidney disease in people with diabetes is usually understood to involve several progressive stages, beginning with microalbuminuria, then proteinuria, eventually leading to end-stage kidney disease that requires intervention with hemodialysis or kidney transplantation. Once microalbuminuria develops, over time the quantity of protein in the urine increases until a threshold is reached, which we call proteinuria. It is believed that GFR begins to decrease only after the onset of proteinuria. GFR is a measure of the kidney's function to filter the blood, and therefore, when it becomes critically low, patients need to have their blood filtered by hemodialysis or a transplanted kidney. The onset of proteinuria therefore represents an advanced stage of kidney disease with a much greater risk for needing these advanced therapies.

Post: With the dramatic increase in obesity, we are facing an epidemic of kidney disease resulting from type 2 diabetes. How do we deal with this impending disaster?

Perkins: The public health crisis of dealing with the increasing need for end-stage renal disease therapies in the type 2 diabetes population requires three very dedicated strategies. First, the onset of diabetes must be prevented. Second, we must identify early the people who have developed type 2 diabetes through screening of at-risk populations. Third, we must apply strategies for kidney health early in the course of diabetes in those who have developed diabetes.

Obesity is a major cause of type 2 diabetes in North America. Public health strategies for improving eating habits, encouraging active and healthy lifestyles, and screening for diabetes are absolutely crucial, and these strategies need to be applied early in those at risk of diabetes. For example, the "Walk to School" program is one of many strategies for preventing and treating childhood obesity.

The second step is for physicians and patients to participate in screening for diabetes in at-risk populations. For example, the American Diabetes Association recommends that all adults over age 45 have a blood test to screen for diabetes on a regular basis by their healthcare team, and at an earlier age if diabetes risk factors, like obesity, are present.

The third step is to prevent the kidney complications of diabetes by maintaining excellent blood sugar control, screening for microalbuminuria on a yearly basis, and to apply the measures that we have been discussing if microalbuminuria develops--good blood glucose control, blood pressure management, and ACE inhibitor medication.

Post: How do you take your findings and translate it to the patient?

Perkins: Since early recognition of microalbuminuria is very important, the take-home message for people with diabetes is to be knowledgeable about diabetes and to be proactive with medical care. In people, it is essential to have a urine test for microalbuminuria every year, and to request the result. Unregulated blood sugar control is the major risk factor for the development of microalbuminuria and kidney disease, so in addition to regular review of home blood sugar tests reviewed by care providers, blood sugar control must be assessed regularly using the glycated hemoglobin A[sub1c] test. The hemoglobin A[sub1c] will help ensure that treatment goals are being met. People should be certain that their blood pressure is monitored at each visit.

To summarize, a person with diabetes should always know the result of his or her last Ale and last microalbuminuria test. In considering the other chronic complications of diabetes--eye, nerve, and heart diseases--patients should be sure to regularly have an eye exam with an ophthalmologist, have their feet examined by their doctor, and be aware of cholesterol and blood pressure levels. I think that knowledge of this simple "diabetes checklist" would be a first step to facilitating proactive care and help people with diabetes to reduce their own risk of complications like kidney disease.


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