CME
Diabetic Nephropathy

Jointly sponsored by The Dulaney Foundation and
Diabetic Microvascular Complications Today.
Release Date: December 2004. Expiration Date: December 31, 2005.
This continuing medical education activity is supported by an unrestricted educational grant from Eli Lilly and Company.
By Mohamed Atta, MD

STATEMENT OF NEED

Diabetes is responsible for 50% of the patients on dialysis in the United States (Figure 1). This trend is likely to continue, as the World Health Organization (WHO) projects a 46% increase in the number of people with diabetes worldwide by 2010.

Microalbuminuria may be a marker for early generalized endothelial damage as well as diabetic nephropathy (DN), and its early detection has important practical implications. The management of DN should target all risk factors, not just specific organs. Optimal blood pressure control is a key to managing the diabetic patient at risk for kidney disease, as is treatment targeting hyperglycemia, dyslipidemia and antismoking efforts.

TARGET AUDIENCE

This activity is designed for primary care physicians, endocrinologists, cardiologists and nephrologists.

LEARNING OBJECTIVES

After successful completion of this program, the participant should be able to:
• discuss the implications of DN and end stage renal disease (ESRD);
• describe the concept of microalbuminuria and how it develops;
• list the criteria for diagnosing microalbuminuria and the recommendations for screening; and
• review the clinical trials that form the basis for treatment of patients with microalbuminuria.

METHOD OF INSTRUCTION

Participants should read the learning objectives and CME program in their entirety. After reviewing the material, they must complete the self-assessment test, which consists of a series of multiple-choice questions.
Upon completing this activity as designed and achieving a passing score of 70% or higher on the self-assessment test, participants will receive a CME credit letter awarding AMA/PRA category 1 credit and the test’s answer key 4 weeks after the registration and evaluation materials are received.

The estimated time to complete this activity as designed is 1 hour.

ACCREDITATION

This activity has been planned and implemented in accordance with the essentials and standards of the ACCME through the joint sponsorship of The Dulaney Foundation and Diabetic Microvascular Complications Today.

DISCLOSURE

In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and FDA guidelines, all program faculty are required to disclose to the activity participants: 1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices, or providers of commercial services, that relate to the content of their presentation/material or the commercial contributors of this activity, and 2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

FACULTY DISCLOSURE DECLARATIONS

The physician faculty whose material appears in this program has a financial interest, relationship or affiliation in the following forms:

Dr. Atta has had consultant relationships with the following companies: Pfizer (New York), Orthobiotech (Bridgewater, NJ), Amgen (Thousand Oaks, Calif) and Scios (Fremont, Calif).

FACULTY CREDENTIALS

Mohamed G. Atta, MD, is an assistant professor of medicine at the Johns Hopkins School of Medicine, division of nephrology. Address all correspondence to 1830 E Monument St, Suite 416, Baltimore, MD 21205; phone: 410-955-5268; fax: 410-955-0485; e-mail: matta1@jhmi.edu.

INTRODUCTION

According to the United States Renal Data System, there is a progressive increase in the incidence of ESRD among patients with diabetes mellitus (DM).1 The majority of these patients have type 2 DM because of factors that include the aging population, increased survival of diabetic patients, and the obesity epidemic. Currently, DM is responsible for 50% of the patients on dialysis in the United States. This trend is likely to continue as WHO projects a 46% increase in the number of people with diabetes worldwide by 2010. It is estimated that 30% to 40% of patients with type 1 diabetes develop DN. Its prevalence varies among patients with type 2 diabetes depending on ethnic group.

CLINICAL COURSE

The natural history of DN (Table 1) is predictable in type 1 diabetes. Classically, there is a functional increase in glomerular filtration rate in the first 5 years after diagnosis that can be associated with microalbuminuria. Overt proteinuria follows in 10 to 15 years, followed by azotemia in 15 to 20 years, and ultimately ESRD in 20 to 25 years. This pattern supports microalbuminuria being the first clinical sign of DN.

A group from Spain, however, presented findings suggesting that changes in the circadian pattern of blood pressure (BP) in type 1 diabetic patients may predict development of albuminuria.2 The authors showed that a relative increase in nocturnal BP precedes the subsequent development of microalbuminuria. They prospectively followed a cohort of 75 patients with type 1 diabetes who had normal BP measured by ambulatory BP monitoring and normal urinary albumin excretion (UAE) at enrollment. Over time, microalbuminuria developed in 14 patients and those without a nocturnal dip in BP were more likely to develop microalbuminuria.

EARLIEST SIGN OF DN

The results suggest that nocturnal hypertension may in fact be the earliest sign of DN. Currently, Medicare covers the cost of ambulatory BP monitoring to only rule out white coat hypertension. Microalbuminuria, therefore, remains for now the predictive tool used to identify patients with early DN.

MICROALBUMINURIA MARKER

The concept of microalbuminuria was introduced more than 30 years ago when it became possible to measure urinary albumin below the level of detection by a urinary dipstick. Microalbuminuria, defined as a UAE of >300 mg in a 24-hour urinary collection, was subsequently shown to be an early marker of DN. This was first described in patients with type 1 diabetes. As the studies expanded to those patients with type 2 DM, microalbuminuria was found, quite remarkably, to be a stronger predictor of cardiovascular mortality than of renal events. In fact, depending upon the degree of albuminuria, the death rate from cardiac events increased from 100% to 150%.3 In the Heart Outcomes Prevention Evaluation (HOPE) Study, microalbuminuria was the strongest predictor of cardiovascular events in a high-risk population with underlying atherosclerosis, stronger than other risk factors such as coronary artery disease or diabetes.4

MICROALBUMINURIA AS A PREDICTOR

It is important to appreciate that microalbuminuria not only predicts cardiovascular events but also other atherosclerotic vascular events. Miettinen et al. followed over 2,000 diabetic and nondiabetic patients for 7 years, looking at the association of the different degrees of proteinuria and atherosclerotic vascular events.5 In both groups, microalbuminuria was associated with increased incidence of cardiovascular events, stroke and aggregate vascular events. Clinical proteinuria increased the incidence of amputation.

TRADITIONAL RISK FACTORS

Compared to traditional risk factors, microalbuminuria has been shown to be a strong predictor of cardiovascular death in healthy populations.6 In a cohort of healthy individuals, Borch-Johnsen et al. prospectively followed more than 2,000 patients for 10 years. The participants had no ischemic heart disease or diabetes. In this study, microalbuminuria increased the relative risk of cardiovascular death by 2.3-fold, independent of other risk factors. These data strongly suggest that microalbuminuria is not only a predictor of renal events in diabetic patients, but is also a much stronger predictor of macrovascular or cardiac events: the most common causes of death in this population.

It is conceivable that extravasation of microalbuminuria across the capillary wall marks the leak of albumin and other macromolecules such as oxidized low-density lipoproteins at other vascular beds that promote further vascular injury. By this logic, microalbuminuria, easily measurable in urine, is a likely marker of generalized endothelial dysfunction in the circulation at large. The good news is that the onset of microalbuminuria in diabetic patients does not seal the fate of the patients as previously proposed. In fact, Perkins observed regression of microalbuminuria (defined as 50% reduction in urinary albumin excretion) between successive 2-year periods.7 At the end of 6 years, the cumulative incidence of regression was 58%. Regression was seen in patients of young age, with short duration of microalbuminuria, low HbA1c, low systolic BP (SBP), and either low cholesterol or triglycerides. As one would expect, patients with low HbA1c, low SBP, and either low cholesterol or triglycerides had a hazard ratio for regression of 3 versus those patients with none of these factors.

RECOMMENDATIONS FOR SCREENING

It is recommended that clinicians obtain standard urinalysis on a yearly basis 5 years after the onset of diagnosis in type 1 diabetic patients and at the time of diagnosis in those with type 2 diabetes. If urinalysis is positive for protein by dipstick reaction, quantification of proteinuria with 24-hour urine collection or protein-to-creatinine ratio should follow. If standard urinalysis is negative, a nontimed screening for microalbuminuria is advised. There is no need for microalbuminuria testing if the standard urinalysis test for protein is positive (Figure 2).

TREATMENT STRATEGIES

The benefit of inhibiting the renin-angiotensin system was first determined by Ed Lewis, MD in his landmark study in 1993.8 In this study, 409 patients with type 1 diabetes were randomized in a double-blind fashion to placebo or captopril. Patients assigned to captopril had a risk reduction of doubling serum creatinine by 48%.

This benefit of inhibiting the renin-angiotensin system was subsequently extended to patients with type 2 diabetes. The Reduction of Endpoints in NIDDM with the AII Antagonist Losartan (RENAAL) study was one of three studies published in the same issue of the New England Journal of Medicine in 2001.9 All three studies evaluated angiotensin receptor blockers (ARBs) on the progression of DN. In RENAAL, the use of losartan resulted in a 28% reduction in risk development of ESRD.

The advantage of beta-blockers was revealed in the longest running study on type 2 diabetic patients ever performed. The United Kingdom Prospective Diabetes Study (UKPDS) showed no difference in the use of the beta-blocker tenormin, or the angiotension-converting enzyme (ACE) inhibitor captopril, on either fatal or nonfatal clinical endpoints or death related to diabetes.10 Renal outcome measures were not significantly different in both groups.

NEW TREATMENT PARADIGM

Our management strategies of DN, however, should shift to a new treatment paradigm that targets all risk factors rather than specific organs in isolation. This multifactorial approach has been proven to be successful. The Steno study from Denmark compared intensive treatment targeting hyperglycemia, dyslipidemia, smoking and hypertension to conventional therapy.11 Aspirin was also administered to the intensive group for secondary prevention. Despite the good intentions, only cholesterol and SBP were significantly improved in the intensive group. Even with this limited success, however, cardiovascular events were reduced by 50%, and there was >50% reduction in several microvascular complications including autonomic neuropathy, retinopathy and nephropathy.

Optimal BP control is clearly one of the most important issues that should be addressed by all primary care physicians, endocrinologists, cardiologists and nephrologists. Approximately 11 million Americans have both DM and hypertension, which increases the risk of macro- and microvascular complications including stroke, coronary artery disease, peripheral vascular disease, retinopathy and nephropathy.12,13 The National Kidney Foundation recommends a target blood pressure of <125/75 mm Hg, which is slightly less than the recommendation by the American Diabetes Association of <130/80 mm Hg.

SUMMARY

In conclusion, microalbuminuria may be a marker for early generalized endothelial damage as well as DN, and its early detection has important practical implications. Once overt nephropathy is detected, treatment should focus on reducing the risk of disease progression. Treatment strategies should focus on a multifactorial approach to simultaneously target hyperglycemia, dyslipidemia and hypertension, in addition to lifestyle modification and inhibition of the renin-angiotensin system.

1. USRDS: the United States Renal Data System. Am J Kidney Dis 2003; 42(6 suppl 5): 1-230.
2. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med. 2002; 347: 797-805.
3. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.
4. Yusuf S, Sleight P, Pogue J, et al. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
5. Miettinen H, Haffner SM, Lehto S, et al. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27:2033-2039.
6. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, et al. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.
7. Perkins BA, Ficociello LH, Silva KH, et al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003;348:2285-2293.
8. Lewis EJ, Hunsicker LG, Bain RP, et al. The Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462.
9. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
10. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713-720.
11. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.
12. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39 (2 Suppl 1): S1-266.
13. Molitch ME, DeFronzo RA, Franz MJ, et al. Diabetic nephropathy. Diabetes Care. 2003; 26 (suppl 1): S94-98.
To obtain the CME Questions and Registration / Evalution Form please click the button above to download a PDF version of the form.
Mohamed Atta, MD
Figure 1. Primary diagnoses for patients who start dialysis.