- Email: [email protected]
Treating the kidney to cure the heart
review
http://www.kidney-international.org & 2008 International Society of Nephrology
Treating the kidney to cure the heart Paolo Cravedi1,2 and Giuseppe Remuzzi1,2 1
Clinical Research Centre for Rare Diseases ‘Aldo e Cele Dacco`’, Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy and 2Unit of Nephrology, Azienda Ospedaliera, Ospedali Riuniti, Bergamo, Italy
The incidence of chronic renal and cardiovascular diseases is increasing worldwide. Since renal disease is the strongest risk factor for cardiovascular morbidity and mortality, strategies able to reduce renal disease progression are expected to translate into a decreased incidence of cardiovascular events. To this purpose, inhibition of the renin–angiotensin system, both by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, represents the best available option. Several large, randomized studies have convincingly shown that these treatments are associated with a significant reduction in the risk for renal disease progression in diabetic and non diabetic patients with chronic kidney disease. Importantly, improvement of renal outcomes is paralleled by a reduction of the cardiovascular risk. However, a significant proportion of patients with chronic nephropathies still progresses to end-stage renal failure or dies for cardiovascular events. A more complex strategy, including strict control of BP and proteinuria, lowering of blood lipids, tight metabolic control of diabetes, and lifestyle changes may improve morbidity and mortality of patients with chronic renal disease as compared with single or dual intervention on the renin–angiotensin system. Moreover, prevention strategies are urgently needed to face the burden of chronic renal disease and cardiovascular morbidity and mortality. This is particularly true for developing countries, where the incidence of these chronic diseases is growing with the highest rate. Kidney International (2008) 74 (Suppl 111), S2–S3; doi:10.1038/ki.2008.511 KEYWORDS: chronic renal disease; cardiovascular disease; proteinuria; renin–angiotensin system inhibitors; hypertension; prevention
Correspondence: Giuseppe Remuzzi, ‘Mario Negri’ Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. E-mails: [email protected] and [email protected] S2
According to projections carried out by World Health Organization (WHO), the world will experience a substantial shift in the distribution of deaths from communicable diseases to noncommunicable diseases during the next 25 years.1 Increased population aging, along with related chronic morbidities such as renal and cardiovascular (CV) diseases, mainly accounts for this changing scenario.1 Patients with chronic renal failure carry one of the heaviest burdens of CV disease, which frequently leads to death before end-stage renal disease is reached. Indeed, a large population study2 showed that the lower the level of estimated glomerular filtration rate, the higher the risk of death, CV events, and hospitalization. Importantly, renal impairment is almost invariably associated with an increased loss of proteins in the urine. This is both a sign of established kidney damage and a direct pathogenic factor in the progression of renal and CV diseases,3 through the induction of a self-perpetuating process of progressive kidney dysfunction and accelerated atherosclerosis.4 Along with proteinuria, hypertension represents the other major determinant of both renal disease progression and CV morbidity and mortality. Thus, antihypertensive agents that are able to reduce urinary protein loss are expected to improve, at the same time, renal and CV outcomes. In this line, a tremendous body of research, both experimental and clinical, has unequivocally shown that pharmacologic blockade of the renin–angiotensin system (RAS) decreases proteinuria, slows progressive renal function loss, and reduces CV risk more effectively than other antihypertensive treatments.5 Two classes of antihypertensive drugs that block the RAS are in clinical use, namely the angiotensin-converting enzyme inhibitors (ACEi) and the angiotensin II receptor blockers. In addition to the antihypertensive effect, RAS inhibition exerts specific effects in the vasculature6 and in the kidney, that is decreased intraglomerular pressure, improved glomerular barrier size-selectivity, which eventually result in reduction of proteinuria.7 In nondiabetic renal disease, there is a clear renoprotective advantage of ACEi as compared with antihypertensive therapies not interfering with the RAS. The Ramipril Efficacy In Nephropathy (REIN) study included 352 patients with chronic nephropathies, primarily of nondiabetic origin, and these were randomized to treatment with the ACEi ramipril or placebo along with other antihypertensive agents. The main finding was that ramipril treatment resulted in Kidney International (2008) 74 (Suppl 111), S2–S3
review
P Cravedi and G Remuzzi: Treating the kidney to cure the heart
reduction of proteinuria and in a slower decline in glomerular filtration rate compared with placebo, despite equivalent blood pressure control.8 A later analysis indicated that a subset of patients on prolonged treatment with ramipril even experienced an improvement of glomerular filtration rate,9 suggesting that remission and even regression of chronic proteinuric nephropathies are feasible goals. Similarly, in diabetic patients, therapy with RAS inhibitors was able to prevent the development of microalbuminuria and to slow the progression from micro- to macroalbuminuria and to overt nephropathy.10 It can be noted that the Heart Outcomes Prevention Evaluation (HOPE) study showed that, among patients at high risk for CV events, those with impaired renal function (serum creatinine X1.4 mg per 100 ml) were the ones who had the highest reduction of CV death and myocardial infarction on ramipril therapy.11 An intensive, multimodal approach including strict blood pressure control, dual RAS inhibition with maximal tolerated doses of ACEi and angiotensin II receptor blockers, glucose (in diabetics) and lipid control, and lifestyle changes might be more effective than single-drug RAS inhibition. In this line, a target-driven, long-term (mean follow-up: 7.8 years), and intensified intervention aimed at multiple risk factors in 80 patients with type II diabetes and microalbuminuria reduced the risk of nephropathy and CV and microvascular events by about 50%.12 In another long-term matchedcohort study of 112 diabetic and nondiabetic patients with severe proteinuric chronic kidney disease and high risk for progression to end-stage renal disease, a multifactorial approach—named Remission Clinic—significantly slowed glomerular filtration rate and reduced the risk for terminal kidney failure by 8.5-fold compared with a conventional regimen of ACEi alone titrated to blood pressure.13 Importantly, most of the patients receiving this multimodal strategy were projected not to progress to end-stage renal disease within the expected lifetime. The Remission Clinic approach, however, failed to appreciably affect proteinuria and disease progression in type II diabetic patients with overt nephropathy. This finding is consistent with the experimental evidence that late ACEi treatment of rats with diabetic nephropathy is effective only in the early phases of the disease, highlighting the importance of prevention and early treatment, even before microalbuminuria has been established.14 This is particularly true for the developing countries, where the dramatic increase in diabetes and hypertension owing to urbanization and changes in lifestyle are expected to translate into a further increase in renal and CV disease and
Kidney International (2008) 74 (Suppl 111), S2–S3
related mortality. Hence, the Commission on Global Advancement of Nephrology (COMGAN) of the International Society of Nephrology (ISN) is developing a global early detection and intervention program for emerging nations that would be implemented according to the peculiar needs and organization facilities of the given country.15 This kind of population screening is expected to help detect a significant proportion of underdiagnosed individuals with renal or CV diseases, especially where health systems are less sophisticated.15 DISCLOSURE
All the authors declared no competing interests. REFERENCES 1. 2.
3. 4.
5.
6. 7.
8.
9.
10.
11.
12.
13. 14.
15.
World Health Statistics 2007. Available at http://www.who.int/whosis/ whostat/2007/en/index.html. Accessed on 15 June 2008. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–1456. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006; 116: 288–296. Remuzzi G, Perico N, Macia M et al. The role of renin–angiotensin– aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl 2005; 99: S57–S65. Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res 2007; 101: 441–454. Pisoni R, Ruggenenti P, Sangalli F et al. Effect of high dose ramipril with or without indomethacin on glomerular selectivity. Kidney Int 2002; 62: 1010–1019. Ruggenenti P, Perna A, Mosconi L et al. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349: 1857–1863. Ruggenenti P, Perna A, Benini R et al. In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia. J Am Soc Nephrol 1999; 10: 997–1006. Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol 2006; 17: S90–S97. Mann JF, Gerstein HC, Pogue J et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Ann Intern Med 2001; 134: 629–636. 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. Ruggenenti P, Perticucci E, Cravedi P et al. Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol 2008; 19: 1213–1224. Perico N, Amuchastegui SC, Colosio V et al. Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J Am Soc Nephrol 1994; 5: 1139–1146. Codreanu I, Perico N, Sharma SK et al. Prevention programmes of progressive renal disease in developing nations. Nephrology (Carlton) 2006; 11: 321–328.
S3
http://www.kidney-international.org & 2008 International Society of Nephrology
Treating the kidney to cure the heart Paolo Cravedi1,2 and Giuseppe Remuzzi1,2 1
Clinical Research Centre for Rare Diseases ‘Aldo e Cele Dacco`’, Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy and 2Unit of Nephrology, Azienda Ospedaliera, Ospedali Riuniti, Bergamo, Italy
The incidence of chronic renal and cardiovascular diseases is increasing worldwide. Since renal disease is the strongest risk factor for cardiovascular morbidity and mortality, strategies able to reduce renal disease progression are expected to translate into a decreased incidence of cardiovascular events. To this purpose, inhibition of the renin–angiotensin system, both by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, represents the best available option. Several large, randomized studies have convincingly shown that these treatments are associated with a significant reduction in the risk for renal disease progression in diabetic and non diabetic patients with chronic kidney disease. Importantly, improvement of renal outcomes is paralleled by a reduction of the cardiovascular risk. However, a significant proportion of patients with chronic nephropathies still progresses to end-stage renal failure or dies for cardiovascular events. A more complex strategy, including strict control of BP and proteinuria, lowering of blood lipids, tight metabolic control of diabetes, and lifestyle changes may improve morbidity and mortality of patients with chronic renal disease as compared with single or dual intervention on the renin–angiotensin system. Moreover, prevention strategies are urgently needed to face the burden of chronic renal disease and cardiovascular morbidity and mortality. This is particularly true for developing countries, where the incidence of these chronic diseases is growing with the highest rate. Kidney International (2008) 74 (Suppl 111), S2–S3; doi:10.1038/ki.2008.511 KEYWORDS: chronic renal disease; cardiovascular disease; proteinuria; renin–angiotensin system inhibitors; hypertension; prevention
Correspondence: Giuseppe Remuzzi, ‘Mario Negri’ Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. E-mails: [email protected] and [email protected] S2
According to projections carried out by World Health Organization (WHO), the world will experience a substantial shift in the distribution of deaths from communicable diseases to noncommunicable diseases during the next 25 years.1 Increased population aging, along with related chronic morbidities such as renal and cardiovascular (CV) diseases, mainly accounts for this changing scenario.1 Patients with chronic renal failure carry one of the heaviest burdens of CV disease, which frequently leads to death before end-stage renal disease is reached. Indeed, a large population study2 showed that the lower the level of estimated glomerular filtration rate, the higher the risk of death, CV events, and hospitalization. Importantly, renal impairment is almost invariably associated with an increased loss of proteins in the urine. This is both a sign of established kidney damage and a direct pathogenic factor in the progression of renal and CV diseases,3 through the induction of a self-perpetuating process of progressive kidney dysfunction and accelerated atherosclerosis.4 Along with proteinuria, hypertension represents the other major determinant of both renal disease progression and CV morbidity and mortality. Thus, antihypertensive agents that are able to reduce urinary protein loss are expected to improve, at the same time, renal and CV outcomes. In this line, a tremendous body of research, both experimental and clinical, has unequivocally shown that pharmacologic blockade of the renin–angiotensin system (RAS) decreases proteinuria, slows progressive renal function loss, and reduces CV risk more effectively than other antihypertensive treatments.5 Two classes of antihypertensive drugs that block the RAS are in clinical use, namely the angiotensin-converting enzyme inhibitors (ACEi) and the angiotensin II receptor blockers. In addition to the antihypertensive effect, RAS inhibition exerts specific effects in the vasculature6 and in the kidney, that is decreased intraglomerular pressure, improved glomerular barrier size-selectivity, which eventually result in reduction of proteinuria.7 In nondiabetic renal disease, there is a clear renoprotective advantage of ACEi as compared with antihypertensive therapies not interfering with the RAS. The Ramipril Efficacy In Nephropathy (REIN) study included 352 patients with chronic nephropathies, primarily of nondiabetic origin, and these were randomized to treatment with the ACEi ramipril or placebo along with other antihypertensive agents. The main finding was that ramipril treatment resulted in Kidney International (2008) 74 (Suppl 111), S2–S3
review
P Cravedi and G Remuzzi: Treating the kidney to cure the heart
reduction of proteinuria and in a slower decline in glomerular filtration rate compared with placebo, despite equivalent blood pressure control.8 A later analysis indicated that a subset of patients on prolonged treatment with ramipril even experienced an improvement of glomerular filtration rate,9 suggesting that remission and even regression of chronic proteinuric nephropathies are feasible goals. Similarly, in diabetic patients, therapy with RAS inhibitors was able to prevent the development of microalbuminuria and to slow the progression from micro- to macroalbuminuria and to overt nephropathy.10 It can be noted that the Heart Outcomes Prevention Evaluation (HOPE) study showed that, among patients at high risk for CV events, those with impaired renal function (serum creatinine X1.4 mg per 100 ml) were the ones who had the highest reduction of CV death and myocardial infarction on ramipril therapy.11 An intensive, multimodal approach including strict blood pressure control, dual RAS inhibition with maximal tolerated doses of ACEi and angiotensin II receptor blockers, glucose (in diabetics) and lipid control, and lifestyle changes might be more effective than single-drug RAS inhibition. In this line, a target-driven, long-term (mean follow-up: 7.8 years), and intensified intervention aimed at multiple risk factors in 80 patients with type II diabetes and microalbuminuria reduced the risk of nephropathy and CV and microvascular events by about 50%.12 In another long-term matchedcohort study of 112 diabetic and nondiabetic patients with severe proteinuric chronic kidney disease and high risk for progression to end-stage renal disease, a multifactorial approach—named Remission Clinic—significantly slowed glomerular filtration rate and reduced the risk for terminal kidney failure by 8.5-fold compared with a conventional regimen of ACEi alone titrated to blood pressure.13 Importantly, most of the patients receiving this multimodal strategy were projected not to progress to end-stage renal disease within the expected lifetime. The Remission Clinic approach, however, failed to appreciably affect proteinuria and disease progression in type II diabetic patients with overt nephropathy. This finding is consistent with the experimental evidence that late ACEi treatment of rats with diabetic nephropathy is effective only in the early phases of the disease, highlighting the importance of prevention and early treatment, even before microalbuminuria has been established.14 This is particularly true for the developing countries, where the dramatic increase in diabetes and hypertension owing to urbanization and changes in lifestyle are expected to translate into a further increase in renal and CV disease and
Kidney International (2008) 74 (Suppl 111), S2–S3
related mortality. Hence, the Commission on Global Advancement of Nephrology (COMGAN) of the International Society of Nephrology (ISN) is developing a global early detection and intervention program for emerging nations that would be implemented according to the peculiar needs and organization facilities of the given country.15 This kind of population screening is expected to help detect a significant proportion of underdiagnosed individuals with renal or CV diseases, especially where health systems are less sophisticated.15 DISCLOSURE
All the authors declared no competing interests. REFERENCES 1. 2.
3. 4.
5.
6. 7.
8.
9.
10.
11.
12.
13. 14.
15.
World Health Statistics 2007. Available at http://www.who.int/whosis/ whostat/2007/en/index.html. Accessed on 15 June 2008. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–1456. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006; 116: 288–296. Remuzzi G, Perico N, Macia M et al. The role of renin–angiotensin– aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl 2005; 99: S57–S65. Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res 2007; 101: 441–454. Pisoni R, Ruggenenti P, Sangalli F et al. Effect of high dose ramipril with or without indomethacin on glomerular selectivity. Kidney Int 2002; 62: 1010–1019. Ruggenenti P, Perna A, Mosconi L et al. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349: 1857–1863. Ruggenenti P, Perna A, Benini R et al. In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia. J Am Soc Nephrol 1999; 10: 997–1006. Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol 2006; 17: S90–S97. Mann JF, Gerstein HC, Pogue J et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Ann Intern Med 2001; 134: 629–636. 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. Ruggenenti P, Perticucci E, Cravedi P et al. Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol 2008; 19: 1213–1224. Perico N, Amuchastegui SC, Colosio V et al. Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J Am Soc Nephrol 1994; 5: 1139–1146. Codreanu I, Perico N, Sharma SK et al. Prevention programmes of progressive renal disease in developing nations. Nephrology (Carlton) 2006; 11: 321–328.
S3