According to the US Renal Data System,

DIABETIC NEPHROPATHY * Mohamed G. Atta, MD ABSTRACT *Based on a presentation given by Dr Atta at a CME dinner symposium for family physicians. Assistant Professor of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to: Mohamed G. Atta, MD, Johns Hopkins University School of Medicine, 18 Building, Suite 416 Renal, 6 N. Wolfe St, Baltimore, MD 21287. E-mail: matta1@jhmi.edu. The prevalence of diabetes-related end-stage renal disease has increased considerably in recent years and is expected to continue to increase over the next decade. Approximately to 4 of persons with type 1 diabetes develop nephropathy. In type 2 diabetes the likelihood of progression to nephropathy varies considerably among different ethnic groups. Microalbuminuria is a significant predictor of subsequent nephropathy in patients with either type 1 or type 2 diabetes, and also predicts increased risk of a number of cardiovascular disease outcomes, including mortality. Recent evidence suggests that microalbuminuria reflects a generalized vascular disease process that is associated with increased development of atherosclerosis and impairment of endothelium-dependent blood flow regulation in clinically healthy patients. Guidelines developed by the American Kidney Foundation recommend annual screening for microalbuminuria beginning at the time of diagnosis in patients with type 2 diabetes, and 5 years after diagnosis in patients with type 1 diabetes. Microalbuminuria can regress spontaneously in many cases; factors that are associated with an increased likelihood of microalbuminuria regression include younger age and lower levels of cholesterol, triglycerides, glycosylated hemoglobin A 1c (HbA 1c ), and systolic blood pressure. First-line treatment strategies for microalbuminuria include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers. The progressive course of nephropathy in patients with diabetes is not inevitable, and more intensive therapy intended to correct multiple risk factors simultaneously can produce a greater reduction in the risk of nephropathy progression than conventional treatment strategies. However, even with intensive treatment, few patients are able to reduce their HbA 1c values below 6.5. (Adv Stud Med. 5;5(4A):S276-S281) According to the US Renal Data System, the incidence of end-stage renal disease (ESRD) associated with diabetes increased markedly during the 199s, a period when the incidence of ESRD associated with hypertension, glomerulonephritis, and cystic kidney all remained relatively constant. 1 Data from the Renal Data System also suggest that approximately 5 of all patients who are on dialysis have a primary diagnosis of diabetes (mostly type 2 diabetes). By comparison, 27 of dialysis patients have hypertension, 13 have glomerulonephritis, and of patients have other causes. 1 The number of persons with ESRD as a result of diabetes is likely to continue to increase for some years to come; the World Health Organization has projected a 46 increase in the worldwide prevalence of diabetes between and, an increase from a global population of 151 million to 221 million people with diabetes. 2 It is estimated that to 4 of patients with type 1 diabetes eventually develop nephropathy. Among S276 Vol. 5 (4A) April 5

patients with type 2 diabetes, the prevalence of diabetic nephropathy varies from approximately 5 to in white patients, to in black patients, to as many as 6 of members in the Pima Indian tribe. 3,4 The progression of diabetic nephropathy among patients with type 1 diabetes is typically very predictable. The glomerular filtration rate (GFR) increases during the first few years of hyperglycemia as a result of hyperfiltration that is associated with microalbuminuria. After approximately years of hyperglycemia, the GFR begins to decrease, and proteinuria develops. Azotemia appears after 15 to years, followed by ESRD after to 25 years. Thus, microalbuminuria is the first manifestation of a long progressive course of gradually worsening kidney function. In general, type 2 diabetes follows this same general course. Data from clinical trials conducted over the last 2 decades suggest that this progressive course of renal dysfunction is not inevitable, and that therapeutic approaches that target a number of modifiable risk factors can slow the progression of nephropathy in patients with diabetes. (9.9-114.9 mm Hg; P =.1). In contrast, patients who did not develop microalbuminuria exhibited a slight decrease in mean systolic blood pressure during sleep (6.4-6. mm Hg; not statistically significant). Patients who exhibited a typical nocturnal decline in blood pressure (defined in this study as a ratio of systolic blood pressure during sleep to systolic blood pressure while awake of.9 or less) had a 7 lower risk of developing microalbuminuria than patients who did not exhibit this normal blood pressure pattern (Figure 1). These findings suggest that nocturnal hypertension may be an early clinical manifestation of the progression of diabetic nephropathy. The link between proteinuria and structural abnormalities of the kidney was first established by Dr Richard Bright (1789-1858), the personal physician to Queen Victoria of England. 6 Bright was also among the first to suspect that the kidneys are important in the development of hypertension. The concept of microalbuminuria was introduced more than 4 years ago when an immunoassay method was first developed MICROALBUMINURIA AND VASCULAR DISEASE The results of a recent study suggest that abnormally elevated blood pressure during sleep may be a significant cause of microalbuminuria in patients with type 1 diabetes. 5 The investigators monitored 75 adolescents and young adults with type 1 diabetes who had normal blood pressures and albumin excretion at baseline over a 5-year period. Blood pressure was measured at baseline and then again 2 years after enrollment in the study using 24-hour ambulatory blood pressure monitoring. In normal individuals, blood pressure decreases during the course of a night s sleep and increases again upon awakening in the morning. In this study, the investigators found the patients who developed microalbuminuria exhibited an increase, rather than a decrease, in mean systolic blood pressure during sleep Figure 1. Increase in Nocturnal Blood Pressure and Progression to Microalbuminuria in Type 1 Diabetes Patients with type 1 diabetes who exhibit a normal nocturnal pattern of blood pressure, characterized by a decrease in blood pressure during sleep and an increase upon awakening, were less likely to progress to microalbuminuria than patients who exhibited an abnormal nocturnal pattern of increased blood pressure during sleep. Reprinted with permission from Lurbe et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med. 2;347(11):797-85. 5 Advanced Studies in Medicine S277

that made it possible to detect albumin in the urine at concentrations lower than could be detected by dipstick. 7 However, it was not until the mid-198s that researchers became interested in microalbuminuria as a predictor for diabetic nephropathy. The relationship between microalbuminuria and nephropathy was first demonstrated in patients with type 1 diabetes and was later extended to patients with type 2 diabetes. In addition, it was subsequently shown that microalbuminuria (urine albumin concentration of -14 µg/l) is actually a very strong predictor of increased cardiovascular mortality. In one study that compared cardiovascular disease outcomes between patients with diabetes and microalbuminuria and normal control subjects, mortality over a 9-year period was increased by 148 in patients with microalbumin concentrations of to 14 µg/l, by 76 in patients with microalbumin concentrations of 16 to 29 µg/l, and by 37 in patients with microalbumin concentrations below 16 µg/l. 8 The association between microalbuminuria and clinical outcomes was also demonstrated in the Heart Outcomes Prevention and Evaluation (HOPE) clinical trial, which evaluated the effects of angiotensin-converting enzyme (ACE) inhibitor therapy and several important cardiovascular risk factors on the incidence of myocardial infarction, stroke, or death from cardiovascular causes in patients with or without diabetes. 9 More than 9 patients who were at high risk of vascular events at baseline (age 55 years, evidence of vascular disease or diabetes, and at least one other cardiovascular risk factor) were randomized to treatment with either ramipril or placebo for 5 years. Microalbuminuria was actually the strongest independent predictor of cardiovascular events in this study, and was associated with a greater increase in the risk of an endpoint event than coronary artery disease or diabetes. Similarly, Borch-Johnsen and colleagues compared microalbuminuria with other traditional risk factors for ischemic heart disease in 85 patients who did not have heart disease, renal disease, urinary tract infection, or diabetes at baseline (Figure 2). After adjusting for other cardiovascular risk factors, the relative risk of ischemic heart disease among patients with microalbuminuria (defined as the group of patients who were in the upper for the urinary albumin/creatinine ratio) was 2.3 (95 confidence interval, 1.3-3.9; P =.2). The likelihood of survival over a -year period was 97 for patients without microalbuminuria and 91 for patients with microalbuminuria (P <.1). Urinary protein excretion also predicts other forms of atherosclerotic disease. This relationship was demonstrated in a study of more than patients with or without diabetes who were evaluated over a 7- year period. 11 Whether patients had diabetes or not, the incidence of coronary heart disease, stroke, amputation, and any atherosclerotic disease event was related to increasing urinary protein concentration (Figure 3). In patients with type 2 diabetes, the incidence of stroke was 7.2 in patients without proteinuria (urinary protein <15 mg/l), 11 in patients with borderline proteinuria (urinary protein 15- mg/l), and 23 in patients with clinical proteinuria (urinary protein > mg/l; for trend). As with hypertension, it has been hypothesized that the clinical consequences of microalbuminuria are related to physical injury to the vascular endothelium of the kidney or other organs. Endothelial injury produces an increase in angiotensin II, which raises singlenephron GFR and promotes the extravasation of Figure 2. Microalbuminuria Compared with Traditional Risk Factors for Ischemic Heart Disease Adjusted Relative Risk 3 2.5 2 1.5 1 2.6 Smoking 2.3 Microalbuminuria N = 85; -year follow-up 2.1 Male Gender 1.6 Total Cholesterol 1.2 Systolic BP The impact of microalbuminuria and other traditional risk factors on the risk for ischemic heart disease among patients free from heart disease, renal disease, urinary tract infection, or diabetes at baseline. Data from Borch-Johnsen et al. S278 Vol. 5 (4A) April 5

albumin (and other substances, such as oxidized lowdensity lipoprotein) into Bowman s capsule. By analyzing the albumin content of urine, it is relatively easy to measure albumin extravasation in the kidneys. A similar process of albumin extravasation may also occur at other vascular sites throughout the body, although it is more difficult to measure albumin extravasation in other tissues. In one study, the extent of systemic transvascular albumin leakage was estimated in patients with severe atherosclerosis and in healthy control subjects by examining the disappearance of radioactively labeled albumin from the vascular compartment over a 1-hour period. 12 Patients with atherosclerosis exhibited a significant increase in transvascular albumin leakage that was significantly correlated with albumin excretion in the urine. Transvascular albumin leakage has also been described in subjects who are clinically healthy but with elevated urinary albumin excretion (urinary albumin excretion rate 6.6-15 µg per minute). 13 In addition, microalbuminuria is also associated with impaired flow-associated, endothelium-dependent dilatation of the brachial artery in clinically healthy individuals with microalbuminuria. 14 These findings suggest that microalbuminuria actually reflects a generalized vascular disease state that may promote the development of atherosclerosis by increasing the deposition of lipid in the blood vessel wall, and thereby increasing the risk of a number of different manifestations of vascular disease. SCREENING AND TREATMENT Guidelines for microalbuminuria screening of patients with diabetes have been developed by the National Kidney Foundation. 15 These guidelines recommend that a standard urinalysis be performed 5 years after diagnosis in patients with type 1 diabetes and at the time of diagnosis in patients with type 2 diabetes, and then be repeated at yearly intervals thereafter. If the urine test is positive, proteinuria should be quantified using 24-hour urine or the protein/creatinine ratio. If the standard urinalysis is negative, a nontimed screen for microalbuminuria should be performed. It is not necessary to test for microalbuminuria if standard dipstick testing is positive. Recent evidence suggests that albuminuria may be a modifiable risk factor. There is good evidence to suggest that albuminuria can be modified in patients with renal disease. There are fewer data regarding the modification of albuminuria in patients with cardiovascular or atherosclerotic disease. In many cases, microalbuminuria regresses spontaneously. The incidence of significant regression of microalbuminuria was recently examined in 386 patients with type 1 diabetes who had significant persistent proteinuria during an initial 2-year evaluation period. 16 Over 6 years of evaluation, the cumulative incidence of microalbuminuria regression (defined as a reduction in urinary albumin concentration of at least 5 from one 2- year period to the next) was 58. Several independent factors were associated with an increased likelihood of microalbuminuria regression. These include age 26 Figure 3. Incidence of CHD Events, Stroke, Lower-Extremity Amputation, and All ASVD Events in and NIDD Subjects by Urinary Protein 5 4 5 4 P =.2 CHD Amputation P =.1 5 4 7 6 5 4 Stroke ASVD U-protein <15 mg U-protein <15 mg U-protein < mg CHD = coronary heart disease; ASVD = atherosclerotic vascular disease; NIDD = non insulin-dependent diabetes. Reprinted with permission from Miettinen et al. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27(11):33-39. 11 Advanced Studies in Medicine S279

years or younger, cholesterol level under 198 mg/dl, triglycerides under 145 mg/dl, glycosylated hemoglobin A 1c (HbA 1c ) under 8, and systolic blood pressure under 115 mm Hg. In patients with 3 of these beneficial factors, the incidence of microalbuminuria regression over 6 years was 3 times the rate of regression among patients with no beneficial factors. TREATMENT OF MICROALBUMINURIA First-line treatment strategies for microalbuminuria include ACE inhibitors, angiotensin receptor blockers (ARBs), and beta blockers. An important goal of treatment should be intensive blood pressure control. Other effective strategies include strict glycemic control, a low protein diet, statins, and aspirin. The benefit of ACE inhibitor therapy on the progression of chronic kidney disease was first demonstrated by Lewis and colleagues in patients with type 1 diabetes, urinary protein excretion of 5 mg or more per day, and serum creatinine 2.5 mg/dl or less. 17 Treatment with captopril produced a 48 reduction in the percentage of patients who doubled their serum creatinine (the study primary endpoint) over 4 years of treatment. Captopril appeared to produce a beneficial effect on renal function that was independent of its effect on blood pressure. In patients with type 2 diabetes, the Reduction of End Points in with Angiotensin II Receptor Antagonist Losartan (RENAAL) study examined the effects of angiotensin receptor blockade on the progression of renal disease. 18 Patients with type 2 diabetes and nephropathy at baseline were randomized to double-blind treatment with losartan or placebo, in combination with conventional antihypertensive treatment (calcium-channel blockers, diuretics, alpha blockers, beta blockers, and centrally acting agents) for a mean of 3.4 years. The primary endpoint was the combined incidence of the doubling of serum creatinine from baseline, ESRD, or death. Compared with placebo, treatment with the ARB losartan was associated with a 16 relative reduction in the incidence of the composite primary endpoint (P =.2) and a 28 reduction in the risk of ESRD (P =.2). In another study of patients with type 2 diabetes, a direct comparison of the ACE inhibitor captopril and the beta blocker atenolol found no significant differences between the 2 treatments in the progression to microalbuminuria (31 vs 26 for the captopril and atenolol groups, respectively) or in the progression to overt proteinuria (5 vs ) over 9 years of treatment. 19 Some data suggest that the most effective way to reduce the microvascular complications of diabetes is by combining treatments to address several risk factors simultaneously. A recent study in Denmark compared the effectiveness of an intensified treatment strategy intended to reduce several modifiable risk factors versus conventional therapy in patients with type 2 diabetes and nephropathy. Patients in the intensive therapy group were significantly more likely to attain serum cholesterol of less than 175 mg/dl and systolic blood pressure under 15 mm Hg (P.1). They also tended to have better rates of attaining HbA 1c values under 6.5, triglycerides under 15 mg/dl, and diastolic blood pressure under 8 mm Hg, although these differences were not statistically significant. Patients randomized to the intensive treatment had significantly lower rates of nephropathy (relative risk,.39; P =.3); retinopathy (relative risk,.42; P =.2); and autonomic neuropathy (relative risk,.37; P =.2). The primary endpoint, the combined incidence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation, was reduced by approximately 5 in the intensive therapy group compared with conventional therapy. Although these findings demonstrate that aggressive intervention to modify risk factors can improve the microvascular and macrovascular complications of diabetes more than conventional treatment, it should be noted that even with the intensive treatment used in this study, fewer than of patients were able to attain HbA 1c values below 6.5. Although risk factor modification is clearly important in patients with diabetes, management of hypertension is of particular importance in preventing renal disease. It has been estimated that approximately 11 million Americans have both hypertension and diabetes. The National Kidney Foundation recommends a target blood pressure of less than 125/75 mm Hg 15 ; the American Diabetes Association recommends a target blood pressure of less than 1/8 mm Hg. 21 In patients with hypertension and type 2 diabetes with microalbuminuria and renal insufficiency (serum creatinine >1.5 mg/dl), ARBs delay the progression of nephropathy. Despite the effectiveness of antihypertensive therapy for preventing diabetes complications, many physicians are not using these medications as effectively as they could. A survey of US physicians for S28 Vol. 5 (4A) April 5

their prescribing habits for antihypertensive medications found that only 2 to 3 of primary care physicians reported that they start treatment for their patients with diabetes when the diastolic blood pressure is between 8 and 84 mm Hg; more than half of physicians reported that they would wait until the diastolic blood pressure is 9 to 94 mm Hg; and 3 said that they would wait until diastolic blood pressure was above mm Hg before starting treatment. 22 SUMMARY AND CONCLUSIONS The clinical course of diabetic nephropathy is typically characterized by a gradual decline in renal function that eventually culminates in ESRD. However, this clinical course is not inevitable. By controlling hyperglycemia it is possible to change the course of diabetic nephropathy; and by targeting many risk factors simultaneously, the progression of renal disease can be slowed in many patients. Considerable evidence now suggests that microalbuminuria is not simply a predictor of diabetic nephropathy, but is rather a marker for more generalized endothelial damage. Once diabetic nephropathy has been identified, management should focus on correcting several risk factors for progression. These should include lifestyle modification, tight control of blood glucose, cholesterol, and blood pressure, with the addition of medication to inhibit the renin-angiotensin system. REFERENCES 1. United States Renal Data System. Available at: http://www.usrds.org. 2. World Health Organization. Diabetes. Available at: http://www.who.int/dietphysicalactivity/publications/facts /diabetes/en/. Accessed December, 4. 3. US Renal Data System. USRDS 2 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, Md: NIH, NIDDK;3. 4. Cowie CC, Port FK, Wolfe RA, Savage PJ, Moll PP, Hawthorne VM. Disparitis in incidence of diabetic endstage renal disease according to race and type of diabetes. N Engl J Med. 1989;321(16):74-79. 5. 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. 2;347(11):797-85. 6. Bright R. Cases and observations, illustrative of renal disease accompanied with the secretion of albuminous urine. London Med Gazette. 1835;18(1835-1836):72-74. 7. Keen H, Chlouveraks C. An immunoassay method for urinary albumin at low concentrations. Lancet. 1963; 186:913-914. 8. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;3(6):356-36. 9. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. ;342(3):145-153. Errata in: N Engl J Med. ;342(18):1376; N Engl J Med. ; 342():748.. Borch-Johnsen K, Feldt-Rasmussen B, Standgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997. 11. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulindependent diabetic subjects. Stroke. 1996;27(11): 33-39. 12. Jensen JS. Renal and systemic transvascular albumin leakage in severe atherosclerosis. Arterioscler Thromb Vasc Biol. 1995;15(9):1324-1329. 13. Jensen JS, Borch-Johnsen K, Jensen G, Feldt-Rasmussen B. Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects. Clin Sci (Lond). 1995;88(6):629-633. 14. Clausen P, Jensen JS, Jensen G, Borch-Johnsen K, Feldt- Rasmussen B. Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation. 1;3(14):1869-1874. 15. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2;39(2, suppl 1):S1-S266. 16. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 3;348(23):2285-2293. 17. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-1462. Erratum in: N Engl J Med. 1993;3(2):152. 18. 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. 1;345(12):861-869. 19. 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(716):713-7.. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 3;348(5):383-393. 21. Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH; American Diabetes Association. Diabetic nephropathy. Diabetes Care. 3;26(suppl 1):S94-S98. 22. Hyman DJ, Pavlik VN. Self-reported hypertension treatment practices among primary care physicians: blood pressure thresholds, drug choices, and the role of guidelines and evidence-based medicine. Arch Intern Med. ;16(15):2281-2286. Advanced Studies in Medicine S281

NOTES S282 Vol. 5 (4A) April 5