- Email: [email protected]
Metabolic pathogenesis of cardiorenal disease
Metabolic Pathogenesis of Cardiorenal Disease William F. Keane, MD ● Clinical data have established microalbuminuria/proteinuria as an independent risk factor for the development and progression of renal disease in patients with either diabetes or essential hypertension. Decreased kidney function is associated with increased cardiovascular risk, even at modest reductions in estimated creatinine clearance (to approximately 60 mL/min/1.73 m2) or modest elevations in serum creatinine (>1.4 mg/dL). Treatment with angiotensin-converting enzyme inhibitors has been shown in clinical trials to delay or stabilize the rate of progression of renal disease. Reduction in cardiovascular events, such as stroke and myocardial infarction, also has been shown in these high-risk individuals. These effects are dependent and independent of blood pressure control, suggesting a nonhemodynamic effect in blockade of the renin-angiotensin system. In conjunction with other therapeutic interventions, such as dietary modification and control of serum lipids, it appears that for at least a subgroup of patients it is possible to delay or prevent progression of kidney failure. There frequently is a clustering of risk factors in these individuals, including insulin resistance, salt sensitivity, hypertension, and dyslipidemia. The mechanism of the relationship between albuminuria and cardiovascular disease is unclear but may be related to endothelial cell dysfunction. Nonetheless, the presence of microalbuminuria/proteinuria as a marker for cardiovascular disease has important implications for the identification and treatment of individuals at risk. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Cardiovascular disease; progressive kidney disease; microalbuminuria; proteinuria; diabetes mellitus; insulin resistance; dyslipidemia.
I
N THE 1990S, MANY clinical trials and epidemiologic studies showed a relationship between kidney disease and cardiovascular disease. Initially, these studies focused on albuminuria as a risk factor for cardiovascular disease, but more recent evidence has indicated that subtle changes in serum creatinine also identify a group of individuals who are at potentially increased risk for cardiovascular disease.1 Numerous studies have shown a relationship between the presence of elevated urinary albumin excretion and risk of progression of kidney disease in individuals with diabetes.2-4 In patients with microalbuminuria and essential hypertension, a similar increased risk for cardiorenal disease has been suggested. Reduction of albumin excretion with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists correlates with a plateau of or decrease in the rate of decline of
From the Department of Medicine and Division of Nephrology, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN. Received and accepted as submitted July 17, 2001. Address reprint requests to William F. Keane, MD, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3806-0032$35.00/0 doi:10.1053/ajkd.2001.29260 1372
renal function. This effect appears independent of the antihypertensive effect of these agents.3,5-7 Microalbuminuria also has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 18,9 and type 2 diabetes mellitus10-12 and for patients with essential hypertension.13,14 Epidemiologic studies have shown an association between microalbuminuria and insulin resistance, obesity, salt sensitivity, and dyslipidemia.15 It has been suggested that diffuse endothelial cell dysfunction makes these individuals particularly susceptible to cardiovascular disease.16 In particular, endothelial increased permeability to proteins may explain, in part, these deleterious vascular effects. The reversal of endothelial dysfunction with inhibitors of the renin-angiotensin II system and with lipid-lowering therapy (particularly with the statin class of agents) has important therapeutic implications. It is possible that improvement in endothelial function can be assessed indirectly by monitoring reductions in urine albumin excretion. PATHOGENETIC FACTORS IN CARDIORENAL DISEASE
Essential Hypertension The prevalence of microalbuminuria in patients with essential hypertension is 5% to 37%.13,17-19 The magnitude of microalbuminuria
American Journal of Kidney Diseases, Vol 38, No 6 (December), 2001: pp 1372-1375
SYMPOSIUM PROCEEDINGS
tends to correlate with increasing blood pressure, particularly when 24-hour ambulatory measurements are performed.13,17 Patients with essential hypertension and microalbuminuria also have increased carotid artery wall thickness,20 left ventricular hypertrophy, nonfatal myocardial infarcts, and peripheral vascular disease.17 A significant positive correlation between urinary albumin levels, fasting serum insulin levels, and severity of angiographically shown coronary artery disease has been shown.21 Hyperinsulinemia and microalbuminuria were predictive for significantly increased risk of coronary artery disease.21 Patients with newly diagnosed essential hypertension and with microalbuminuria tended to be older, with a higher body mass index and a family history of essential hypertension. They also were more likely to smoke and have a sedentary lifestyle than patients without microalbuminuria.22 Many of these patients have been found to have insulin resistance, hyperinsulinemia, the loss of nocturnal dipping of blood pressure, and dyslipidemia.17,23 Hypertensive patients with microalbuminuria have higher nocturnal blood pressure measurements and significantly higher plasma glucose levels, serum insulin levels, and serum lipoprotein(a) levels than hypertensive patients without microalbuminuria and normotensive control subjects. A significant positive correlation exists among urinary albumin excretion, insulin area under the curve, and 24-hour diastolic blood pressure.23 Elevation of apolipoprotein B–containing lipids and decreased highdensity lipoproteins are seen commonly in essential hypertension patients with microalbuminuria.17 The relationship between this dyslipidemia and microalbuminuria is not well understood. It is not explained by obesity or increased body mass, but it may be secondary to the insulin resistance and hyperinsulinemia seen in these patients.17,24 Studies have shown that microalbuminuria is found in salt-sensitive patients and in patients who cannot regulate their hemodynamic responses to a sodium load. Of particular interest is that both of these groups of patients share other metabolic abnormalities, such as hyperinsulinemia and alterations of the Na⫹/Li⫹ countertransporter.17 Salt-sensitive patients showed increased insulin secretion compared with salt-resistant
1373
patients and excreted a larger amount of urinary albumin and had higher levels of cholesterol and low-density lipoprotein cholesterol.24,25 Diabetes Mellitus Microalbuminuria in patients with type 1 or type 2 diabetes is a useful marker for patients at greatest risk for the development of microvascular and macrovascular disease. For patients with insulin-dependent diabetes mellitus, the onset of microalbuminuria without overt proteinuria or decreased renal function is associated with the hyperfiltration of early diabetic nephropathy.8,17 Many studies have shown that microalbuminuria in insulin-dependent diabetes mellitus appears to be an early marker of glomerular injury and presages macroalbuminuria and progressive renal disease.17 The same likely is true for patients with non–insulin-dependent diabetes mellitus.17 Similar to patients with essential hypertension and microalbuminuria, a cluster of metabolic abnormalities, including hypertension, dyslipidemia, insulin resistance, and coagulation abnormalities, have been identified in diabetic patients with microalbuminuria. Because these also are cardiovascular risk factors, it is not surprising that these patients exhibit a higher incidence of coronary artery disease than patients without microalbuminuria or even nondiabetic patients who also are microalbuminuric.17,21 Endothelial Cell Dysfunction Many authors have suggested that microalbuminuria may be a marker of systemic vascular endothelial dysfunction.4,16 McFarlane et al15 hypothesized that microalbuminuria may indicate generalized cardiovascular and renal endothelial dysfunction and enhanced oxidative stress. The vascular endothelium is involved intimately in hemostasis, fibrinolysis, and vascular permeability. Microalbuminuria is the renal marker for a generalized increase in endothelial permeability that may promote enhanced cardiovascular risk by initiating the process leading to an atherosclerotic plaque. Because dyslipidemia also frequently is present in these patients, its contributory role to this process needs further exploration. An interaction between blood pressure, oxidant stress, and oxidized lipids is proposed as an important factor that could lead to aggressive cardiovascular disease.
1374
WILLIAM F. KEANE
MODIFICATION OF RISK FACTORS
Strategies to decrease cardiovascular morbidity and mortality in patients with microalbuminuria have focused on blood pressure control, particularly with agents that modify the reninangiotensin II system, and treatment of lipids. Many of the factors that are important for cardiovascular disease reduction are independent risk factors for progressive kidney disease. In one randomized trial of patients with essential hypertension, the degree of baseline proteinuria was an important determinant of rate of change of glomerular filtration rate (GFR). Patients with baseline protein excretion of less than 500 mg/24 h had a change in GFR of ⫹2.8 ⫾ 0.4 mL/min/1.73 m2 per year, whereas patients with greater than 500 mg/24 h had a change of ⫺2.1 ⫾ 0.8 mL/min/1.73 m2 per year.26 Ruilope et al4 followed hypertensive patients with and without initial microalbuminuria who were treated with diuretics and -blockers. After 5 years, patients with initial microalbuminuria had a significantly greater decrease in GFR despite similar diastolic and systolic blood pressure levels before and after beginning treatment. The Afro-American Study of Renal Disease stopped the calcium channel blocker arm of that trial because participants who were receiving the ACE inhibitor, ramipril, had greater reduction in proteinuria and better preservation of renal function. This reduction of protein excretion is independent of decreases in blood pressure.27 Benazepril was shown to be effective in delaying progression of renal disease in the ACE Inhibitor in Progressive Renal Insufficiency (APRI) trial. The patients who received the greatest benefit were those with the largest amount of protein excretion at baseline.28 The Ramipril Efficacy in Nephropathy (REIN) trial evaluated the effect of ramipril versus placebo on decrease in renal function and risk of terminal renal failure in proteinuric patients with nondiabetic nephropathy. Patients given ramipril had a slower rate of decline of GFR and a greater reduction in urinary protein excretion that was independent of level of blood pressure control.5 This effect was most evident in patients with massive proteinuria. ACE inhibitors and angiotensin II receptor antagonists are more effective than diuretics, -blockers, and calcium antagonists at decreas-
ing microalbuminuria.4 Schiffrin and Deng compared the effects of ACE inhibition and  blockade on function of small arteries in hypertensive patients and found that ACE inhibitors improved endothelial function in resistance arterioles in hypertensive patients.29 Studies have shown that angiotensin II receptor antagonists also have an antiproteinuric effect in normotensive and hypertensive microalbuminuric subjects7 and patients with type 1 and type 2 diabetic nephropathy.30,31 There is clear evidence that the use of ACE inhibitors and good blood pressure and glycemic control can delay the progression of renal failure in patients with type 1 diabetes.32 The recently completed trials in patients with type 2 diabetic nephropathy will provide new insights regarding the use of angiotensin II receptor antagonists in patients with advanced diabetic disease. Specific trials to evaluate the benefits of treating the dyslipidemia that frequently is present in albuminuric/proteinuric patients with diabetes or essential hypertension have not been performed. Results in small subsets of diabetic patients that have been included in some of the larger lipidlowering trials suggest a potential benefit, however. Trials of lipid-lowering therapy currently are being conducted in end-stage renal disease patients who have the highest cardiovascular risk. These studies should provide new insights into the management of cardiovascular disease in patients with renal disease.33 REFERENCES 1. Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S, for the HOPE Investigators: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril. The HOPE Randomized Trial. Ann Intern Med 134:629-636, 2001 2. Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving H-H, Passa P, Steffes MW, Striker GE, Viberti GC: Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 346:1080-1084, 1995 3. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G: Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Study Epidemiologici in Nefrologia (GISEN). Lancet 352:1252-1256, 1998 4. Ruilope LM, Campo C, Rodriguez-Artalejo F, Lahera V, Garcia Robles R, Rodicio JL: Blood pressure and renal function: Therapeutic implications. J Hypertens 14:12591263, 1996 5. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal
SYMPOSIUM PROCEEDINGS
renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857-1863, 1997 6. Buter H, Navis G, Dullaart RPF, de Zeeuw D, de Jong PE: Time course of the antiproteinuric and renal haemodynamic responses to losartan in microalbuminuric IDDM. Nephrol Dial Transplant 16:771-775, 2001 7. Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851-856, 1999 8. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1:1430-1432, 1982 9. Messent JW, Elliot TG, Hill RG, Jarrett RJ, Keen H, Viberti GC: Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three-year follow-up study. Kidney Int 41:836-839, 1992 10. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356-360, 1984 11. Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrels TJ: Microalbuminuria predicts mortality in non-insulin-dependent diabetics. Diabet Med 1:17-19, 1984 12. Schmitz A, Vaeth M: Microalbuminuria: A major risk factor in non-insulin-dependent diabetes: A ten-year follow-up study of 503 patients. Diabet Med 5:126-134, 1988 13. Gerber LM, Shmukler C, Alderman MH: Differences in urinary albumin excretion rate between normotensive and hypertensive white and non white subjects. Arch Intern Med 152:373-377, 1992 14. Bigazzi R, Bianchi S: Microalbuminuria as a marker of cardiovascular and renal disease in essential hypertension. Nephrol Dial Transplant 10:10-14, 1995 15. McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86:713-718, 2001 16. Keane WF: Proteinuria: Its clinical importance and role in progressive renal disease. Am J Kidney Dis 35:S97S105, 2000 (suppl 1) 17. Bianchi S, Bigazzi R, Campese VM: Microalbuminuria in essential hypertension: Significance, pathophysiology and therapeutic implications. Am J Kidney Dis 34:973995, 1999 18. Bigazzi R, Bianchi S, Campese VM, Baldari GL: Prevalence of microalbuminuria in a large population of patients with mild to moderate essential hypertension. Nephron 61:94-97, 1992 19. Cerasola G, Cottone S, Mule G, Nardi E, Mangano MT, Andronico G, Contorno A, Li Vecchi M, Gaglione P, Renda F, Piazza G, Volpe V, Lisi A, Ferrara L, Panepinto N, Riccobene R: Microalbuminuria, renal dysfunction and cardiovascular complication in essential hypertension. J Hypertens 14:915-920, 1996 20. Bigazzi R, Bianchi S, Nenci R, Baldari D, Baldari G,
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Campese VM: Increased thickness of the carotid artery in patients with essential hypertension and microalbuminuria. J Hum Hypertens 9:827-833, 2001 21. Tuttle KR, Puhlman ME, Cooney SK, Short R: Urinary albumin and insulin as predictors of coronary artery disease: An angiographic study. Am J Kidney Dis 34:918925, 1999 22. Calvino J, Calvo C, Romero R, Gude F, SanchezGuisande D: Atherosclerosis profile and microalbuminuria in essential hypertension. Am J Kidney Dis 34:996-1001, 1999 23. Bianchi S, Bigazzi R, Valtriani C, Chiaponni I, Sgherri G, Baldari G, Natali A, Ferrannini E, Campese VM: Elevated serum insulin levels in patients with essential hypertension and microalbuminuria. Hypertension 23:681687, 1994 24. Bigazzi R, Bianchi S, Baldari G, Campese VM: Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: Role of insulin. Am J Hypertens 9:24-32, 1996 25. Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G, Campese VM: Microalbuminuria in salt-sensitive patients: A marker for renal and cardiovascular risk factors. Hypertension 23:195-199, 1994 26. Toto RD, Mitchell HC, Smith RD, Lee HC, McIntire D, Pettinger WA: “Strict” blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Kidney Int 48:851-859, 1995 27. Keane WF, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation. Am J Kidney Dis 33:1004-1010, 1999 28. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334:939-945, 1996 29. Schiffrin EL, Deng LY: Relationship between smallartery structure and systolic, diastolic and pulse pressure in essential hypertension. J Hypertens 17:381-387, 1999 30. Lozano JV, Llisterri JL, Aznar J, Redon J: Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics. Nephrol Dial Transplant 16:1-5, 2001 31. Fernandez-Andrade C, Russo D, Iversen B, Zucchelli P, Aranda P, Guerra L, Casado S: Comparison of losartan and amlodipine in renally impaired hypertensive patients. Kidney Int 54:S120-S124, 1998 (suppl) 32. 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 329:1456-1462, 1993 33. Keane WF, Brenner BM, Mazzu A, Agro A, for the CHORUS Steering Committee: The CHORUS (Cerivastatin in Heart Outcomes in Renal Disease: Understanding Survival) protocol: A double-blind, placebo-controlled trial in patients with ESRD. Am J Kidney Dis 37:S48-S53, 2001 (suppl 2)
I
N THE 1990S, MANY clinical trials and epidemiologic studies showed a relationship between kidney disease and cardiovascular disease. Initially, these studies focused on albuminuria as a risk factor for cardiovascular disease, but more recent evidence has indicated that subtle changes in serum creatinine also identify a group of individuals who are at potentially increased risk for cardiovascular disease.1 Numerous studies have shown a relationship between the presence of elevated urinary albumin excretion and risk of progression of kidney disease in individuals with diabetes.2-4 In patients with microalbuminuria and essential hypertension, a similar increased risk for cardiorenal disease has been suggested. Reduction of albumin excretion with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists correlates with a plateau of or decrease in the rate of decline of
From the Department of Medicine and Division of Nephrology, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN. Received and accepted as submitted July 17, 2001. Address reprint requests to William F. Keane, MD, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3806-0032$35.00/0 doi:10.1053/ajkd.2001.29260 1372
renal function. This effect appears independent of the antihypertensive effect of these agents.3,5-7 Microalbuminuria also has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 18,9 and type 2 diabetes mellitus10-12 and for patients with essential hypertension.13,14 Epidemiologic studies have shown an association between microalbuminuria and insulin resistance, obesity, salt sensitivity, and dyslipidemia.15 It has been suggested that diffuse endothelial cell dysfunction makes these individuals particularly susceptible to cardiovascular disease.16 In particular, endothelial increased permeability to proteins may explain, in part, these deleterious vascular effects. The reversal of endothelial dysfunction with inhibitors of the renin-angiotensin II system and with lipid-lowering therapy (particularly with the statin class of agents) has important therapeutic implications. It is possible that improvement in endothelial function can be assessed indirectly by monitoring reductions in urine albumin excretion. PATHOGENETIC FACTORS IN CARDIORENAL DISEASE
Essential Hypertension The prevalence of microalbuminuria in patients with essential hypertension is 5% to 37%.13,17-19 The magnitude of microalbuminuria
American Journal of Kidney Diseases, Vol 38, No 6 (December), 2001: pp 1372-1375
SYMPOSIUM PROCEEDINGS
tends to correlate with increasing blood pressure, particularly when 24-hour ambulatory measurements are performed.13,17 Patients with essential hypertension and microalbuminuria also have increased carotid artery wall thickness,20 left ventricular hypertrophy, nonfatal myocardial infarcts, and peripheral vascular disease.17 A significant positive correlation between urinary albumin levels, fasting serum insulin levels, and severity of angiographically shown coronary artery disease has been shown.21 Hyperinsulinemia and microalbuminuria were predictive for significantly increased risk of coronary artery disease.21 Patients with newly diagnosed essential hypertension and with microalbuminuria tended to be older, with a higher body mass index and a family history of essential hypertension. They also were more likely to smoke and have a sedentary lifestyle than patients without microalbuminuria.22 Many of these patients have been found to have insulin resistance, hyperinsulinemia, the loss of nocturnal dipping of blood pressure, and dyslipidemia.17,23 Hypertensive patients with microalbuminuria have higher nocturnal blood pressure measurements and significantly higher plasma glucose levels, serum insulin levels, and serum lipoprotein(a) levels than hypertensive patients without microalbuminuria and normotensive control subjects. A significant positive correlation exists among urinary albumin excretion, insulin area under the curve, and 24-hour diastolic blood pressure.23 Elevation of apolipoprotein B–containing lipids and decreased highdensity lipoproteins are seen commonly in essential hypertension patients with microalbuminuria.17 The relationship between this dyslipidemia and microalbuminuria is not well understood. It is not explained by obesity or increased body mass, but it may be secondary to the insulin resistance and hyperinsulinemia seen in these patients.17,24 Studies have shown that microalbuminuria is found in salt-sensitive patients and in patients who cannot regulate their hemodynamic responses to a sodium load. Of particular interest is that both of these groups of patients share other metabolic abnormalities, such as hyperinsulinemia and alterations of the Na⫹/Li⫹ countertransporter.17 Salt-sensitive patients showed increased insulin secretion compared with salt-resistant
1373
patients and excreted a larger amount of urinary albumin and had higher levels of cholesterol and low-density lipoprotein cholesterol.24,25 Diabetes Mellitus Microalbuminuria in patients with type 1 or type 2 diabetes is a useful marker for patients at greatest risk for the development of microvascular and macrovascular disease. For patients with insulin-dependent diabetes mellitus, the onset of microalbuminuria without overt proteinuria or decreased renal function is associated with the hyperfiltration of early diabetic nephropathy.8,17 Many studies have shown that microalbuminuria in insulin-dependent diabetes mellitus appears to be an early marker of glomerular injury and presages macroalbuminuria and progressive renal disease.17 The same likely is true for patients with non–insulin-dependent diabetes mellitus.17 Similar to patients with essential hypertension and microalbuminuria, a cluster of metabolic abnormalities, including hypertension, dyslipidemia, insulin resistance, and coagulation abnormalities, have been identified in diabetic patients with microalbuminuria. Because these also are cardiovascular risk factors, it is not surprising that these patients exhibit a higher incidence of coronary artery disease than patients without microalbuminuria or even nondiabetic patients who also are microalbuminuric.17,21 Endothelial Cell Dysfunction Many authors have suggested that microalbuminuria may be a marker of systemic vascular endothelial dysfunction.4,16 McFarlane et al15 hypothesized that microalbuminuria may indicate generalized cardiovascular and renal endothelial dysfunction and enhanced oxidative stress. The vascular endothelium is involved intimately in hemostasis, fibrinolysis, and vascular permeability. Microalbuminuria is the renal marker for a generalized increase in endothelial permeability that may promote enhanced cardiovascular risk by initiating the process leading to an atherosclerotic plaque. Because dyslipidemia also frequently is present in these patients, its contributory role to this process needs further exploration. An interaction between blood pressure, oxidant stress, and oxidized lipids is proposed as an important factor that could lead to aggressive cardiovascular disease.
1374
WILLIAM F. KEANE
MODIFICATION OF RISK FACTORS
Strategies to decrease cardiovascular morbidity and mortality in patients with microalbuminuria have focused on blood pressure control, particularly with agents that modify the reninangiotensin II system, and treatment of lipids. Many of the factors that are important for cardiovascular disease reduction are independent risk factors for progressive kidney disease. In one randomized trial of patients with essential hypertension, the degree of baseline proteinuria was an important determinant of rate of change of glomerular filtration rate (GFR). Patients with baseline protein excretion of less than 500 mg/24 h had a change in GFR of ⫹2.8 ⫾ 0.4 mL/min/1.73 m2 per year, whereas patients with greater than 500 mg/24 h had a change of ⫺2.1 ⫾ 0.8 mL/min/1.73 m2 per year.26 Ruilope et al4 followed hypertensive patients with and without initial microalbuminuria who were treated with diuretics and -blockers. After 5 years, patients with initial microalbuminuria had a significantly greater decrease in GFR despite similar diastolic and systolic blood pressure levels before and after beginning treatment. The Afro-American Study of Renal Disease stopped the calcium channel blocker arm of that trial because participants who were receiving the ACE inhibitor, ramipril, had greater reduction in proteinuria and better preservation of renal function. This reduction of protein excretion is independent of decreases in blood pressure.27 Benazepril was shown to be effective in delaying progression of renal disease in the ACE Inhibitor in Progressive Renal Insufficiency (APRI) trial. The patients who received the greatest benefit were those with the largest amount of protein excretion at baseline.28 The Ramipril Efficacy in Nephropathy (REIN) trial evaluated the effect of ramipril versus placebo on decrease in renal function and risk of terminal renal failure in proteinuric patients with nondiabetic nephropathy. Patients given ramipril had a slower rate of decline of GFR and a greater reduction in urinary protein excretion that was independent of level of blood pressure control.5 This effect was most evident in patients with massive proteinuria. ACE inhibitors and angiotensin II receptor antagonists are more effective than diuretics, -blockers, and calcium antagonists at decreas-
ing microalbuminuria.4 Schiffrin and Deng compared the effects of ACE inhibition and  blockade on function of small arteries in hypertensive patients and found that ACE inhibitors improved endothelial function in resistance arterioles in hypertensive patients.29 Studies have shown that angiotensin II receptor antagonists also have an antiproteinuric effect in normotensive and hypertensive microalbuminuric subjects7 and patients with type 1 and type 2 diabetic nephropathy.30,31 There is clear evidence that the use of ACE inhibitors and good blood pressure and glycemic control can delay the progression of renal failure in patients with type 1 diabetes.32 The recently completed trials in patients with type 2 diabetic nephropathy will provide new insights regarding the use of angiotensin II receptor antagonists in patients with advanced diabetic disease. Specific trials to evaluate the benefits of treating the dyslipidemia that frequently is present in albuminuric/proteinuric patients with diabetes or essential hypertension have not been performed. Results in small subsets of diabetic patients that have been included in some of the larger lipidlowering trials suggest a potential benefit, however. Trials of lipid-lowering therapy currently are being conducted in end-stage renal disease patients who have the highest cardiovascular risk. These studies should provide new insights into the management of cardiovascular disease in patients with renal disease.33 REFERENCES 1. Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S, for the HOPE Investigators: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril. The HOPE Randomized Trial. Ann Intern Med 134:629-636, 2001 2. Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving H-H, Passa P, Steffes MW, Striker GE, Viberti GC: Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 346:1080-1084, 1995 3. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G: Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Study Epidemiologici in Nefrologia (GISEN). Lancet 352:1252-1256, 1998 4. Ruilope LM, Campo C, Rodriguez-Artalejo F, Lahera V, Garcia Robles R, Rodicio JL: Blood pressure and renal function: Therapeutic implications. J Hypertens 14:12591263, 1996 5. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal
SYMPOSIUM PROCEEDINGS
renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857-1863, 1997 6. Buter H, Navis G, Dullaart RPF, de Zeeuw D, de Jong PE: Time course of the antiproteinuric and renal haemodynamic responses to losartan in microalbuminuric IDDM. Nephrol Dial Transplant 16:771-775, 2001 7. Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851-856, 1999 8. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1:1430-1432, 1982 9. Messent JW, Elliot TG, Hill RG, Jarrett RJ, Keen H, Viberti GC: Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three-year follow-up study. Kidney Int 41:836-839, 1992 10. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356-360, 1984 11. Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrels TJ: Microalbuminuria predicts mortality in non-insulin-dependent diabetics. Diabet Med 1:17-19, 1984 12. Schmitz A, Vaeth M: Microalbuminuria: A major risk factor in non-insulin-dependent diabetes: A ten-year follow-up study of 503 patients. Diabet Med 5:126-134, 1988 13. Gerber LM, Shmukler C, Alderman MH: Differences in urinary albumin excretion rate between normotensive and hypertensive white and non white subjects. Arch Intern Med 152:373-377, 1992 14. Bigazzi R, Bianchi S: Microalbuminuria as a marker of cardiovascular and renal disease in essential hypertension. Nephrol Dial Transplant 10:10-14, 1995 15. McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86:713-718, 2001 16. Keane WF: Proteinuria: Its clinical importance and role in progressive renal disease. Am J Kidney Dis 35:S97S105, 2000 (suppl 1) 17. Bianchi S, Bigazzi R, Campese VM: Microalbuminuria in essential hypertension: Significance, pathophysiology and therapeutic implications. Am J Kidney Dis 34:973995, 1999 18. Bigazzi R, Bianchi S, Campese VM, Baldari GL: Prevalence of microalbuminuria in a large population of patients with mild to moderate essential hypertension. Nephron 61:94-97, 1992 19. Cerasola G, Cottone S, Mule G, Nardi E, Mangano MT, Andronico G, Contorno A, Li Vecchi M, Gaglione P, Renda F, Piazza G, Volpe V, Lisi A, Ferrara L, Panepinto N, Riccobene R: Microalbuminuria, renal dysfunction and cardiovascular complication in essential hypertension. J Hypertens 14:915-920, 1996 20. Bigazzi R, Bianchi S, Nenci R, Baldari D, Baldari G,
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