Preserving cardiac function in the hypertensive patient: why renal parameters hold the key
Gilles Montalescot* and
Jean-Philippe Collet
Cardiac Care Unit, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France
Received 22 December 2004; revised 10 May 2005; accepted 16 June 2005; online publish-ahead-of-print 8 July 2005.
* Corresponding author. Tel: +33 1 42 16 30 06; fax: +33 1 42 16 29 31. E-mail address: gilles.montalescot{at}psl.ap-hop-paris.fr
 |
Abstract
|
---|
The relationship between cardiovascular and renal pathologies is well recognized in advanced nephropathy and heart failure, but in early disease it has received less attention. Consequently, microalbuminuria screening and interventions that treat early nephropathy remain under-utilized cardioprotective strategies in the hypertensive patient. Agents that delay the progression of renal disease are likely to be cardioprotective by lessening the systemic consequences of renal dysfunction and may have additional cardioprotective effects by exerting beneficial effects on endothelia elsewhere in the body and within the heart. A critical driving factor within both renal and wider cardiovascular pathologies is overactivation of the reninangiotensinaldosterone system (RAAS). Accordingly, RAAS-directed antihypertensive agents including both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been demonstrated to have renoprotective effects. In major prospective trials, two ARBs, losartan and irbesartan, have been demonstrated to be renoprotective in patients with frank proteinuria, and one ARB, irbesartan, has been shown to have renoprotective properties in patients with microalbuminuria. For patients with incipient or frank renal dysfunction, an aggressive RAAS-based approach to hypertension management, combining potent blood pressure control with proven renoprotection, may therefore constitute a key component of therapy targeted towards long-term cardioprotection.
Key Words: Cardiovascular disease Hypertension Microalbuminuria Reninangiotensinaldosterone system Angiotensin receptor blockers ACE-inhibitors
 |
Introduction
|
---|
Hypertensive cardiovascular disease is a systemic condition with potentially devastating long-term effects on vascular and end-organ function. Although the foremost objective of cardiologists concerned with its management is to protect patients against cardiac events and stroke, renal dysfunction is an integral component of the disease and a highly sensitive and predictive marker of its progress. It is therefore surprising that, despite enormous diagnostic and therapeutic potential, renal considerations are still under-utilized by cardiologists in the routine management of hypertension.
Despite being readily available and amenable to intervention, renal parameters are under-exploited in two key ways. Microalbuminuria measurement has yet to become routine for hypertensives, either within the clinic or in the general practice setting. It is a highly sensitive, readily assessed marker of incipient nephropathy and systemic endothelial pathology. It is an independent predictor of either renal failure or cardiovascular morbidity and mortality. Therefore, its measurement should be incorporated within standard management protocols for all patients with hypertension or diabetes.
Sustained renal function should be a key goal of therapeutic intervention in early-stage disease for cardiologists as well as nephrologists. Agents that delay the progression of renal disease are likely to protect against adverse cardiovascular outcomes by protecting against the systemic consequences of renal disease and in addition, may exert beneficial effects on endothelia throughout the vasculature and in the heart.
The relationship between renal and wider cardiovascular diseases is most evident in their advanced stages.1 About half of all patients with congestive heart failure have chronic kidney disease, whereas congestive heart failure is about 15 times more common in patients with chronic kidney disease than in patients with normal renal function.2 Congestive heart failure exacerbates nephropathy, whereas chronic kidney disease is associated with accelerated atherosclerosis, microvessel disease, endothelial dysfunction, and increased sympathetic activity and cardiac pathology.2 Renal artery stenosis and renovascular hypertension may also impact both on the non-stenotic kidney and the heart.3
At the early stages of disease, when a patient may present with few overt pathologies other than hypertension, the relationship between renal and cardiovascular pathologies is also predictive of long-term outcome and is more amenable to successful long-term intervention. Vascular, cerebrovascular, and coronary diseases, ventricular hypertrophy, and ultimately, nephropathy and heart failure are all potential endpoints of a broad syndrome that is symptomatically silent for many years and involves a network of interlocked disease processes, which include sympathetic activation, haemodynamic changes, insulin resistance, inflammatory processes, dyslipidaemia, dysregulation of cytokines and growth factors, and consequent to many of these processes, endothelial damage.47 One of the critical driving factors of this network is increased activity of the reninangiotensinaldosterone system (RAAS), both within the kidney and vascular endothelium. On the basis of this pathophysiological role, it has been posited that RAAS blockade may provide a promising strategy for early therapeutic intervention in hypertensives with renal or atherosclerotic disease.4,7
 |
Search strategy
|
---|
A search of published literature in the last 15 years was performed using the MEDLINE database using the following search terms: cardiovascular disease, hypertension, microalbuminuria, RAAS, nephropathy, and clinical trials. Reference lists from identified studies were also reviewed to identify other potentially relevant references.
 |
Early renal dysfunction and cardiovascular prognosis
|
---|
Microalbuminuria, defined as albumin excretion into the urine at a rate of 20200 µg/min or 30300 mg over 24 h,8 is a critical but under-utilized measure of progression in early renal and cardiovascular disease. Data from several studies in hypertensive and diabetic patients have demonstrated that microalbuminuria is a powerful independent risk factor for cardiovascular disease.9,10 Indeed, even in normotensive, non-diabetic subjects, microalbuminuria has been reported to be associated with dyslipidaemia and elevated insulin consistent with an increased atherogenic risk.11 Albuminuria is correlated with systemic markers of endothelial injury, including fibrinogen, factor VII hyperactivity, and von Willebrand factor.8
Microalbuminuria emerges only after several years of progressive, subclinical, structural, and functional changes within the kidney,12 and represents a critical juncture in the development of cardiovascular disease. Its presence predicts a shift to a more advanced state of pathology, involving frank proteinuria, accelerated atherosclerosis, and endothelial dysfunction, with a significantly increased risk of end-organ damage, major cardiovascular events, and death. Microalbuminuria may be caused by increased glomerular pressure, abnormalities of the glomerular barrier, or impaired albumin resorption, and in most cases can be considered as the earliest measurable manifestation within the kidney of a global abnormality of endothelial function.8
However, not all patients who present with microalbuminuria have identifiable changes in glomerular structure as assessed by electron microscope morphometry. It has been suggested that there is a group of patients in whom microalbuminuria is a consequence of a more general abnormality of the endothelium.13 This hypothesis, which places microalbuminuria within the context of general endothelial dysfunction, is consistent with the predictive relationship between microalbuminuria and vascular disease elsewhere in the body, and may help explain why agents that prevent the progression of microalbuminuria are protective not only of the kidney but other organs.
Microalbuminuria is a common feature in patients both with diabetes and hypertension. It is present in about 40% of hypertensives, particularly those whose blood pressure is poorly controlled, and its prevalence is related to the severity and duration of hypertension.8 Hypertensive patients with microalbuminuria are more likely to have early signs of target-organ damage, including left ventricular hypertrophy and increased carotid artery thickness.14 Even in patients with high-normal blood pressure, the prevalence of microalbuminuria is increased and may predict higher cardiovascular risk.15
In diabetes, microalbuminuria rates are even higher. The recent DEMAND (Developing Education on Microalbuminuria for Awareness of reNal and cardiovascular risk in Diabetes) international survey involving over 32 000 people from 5000 general practitioner clinics showed that 39% of patients with Type 2 diabetes had microalbuminuria and 10% had macroalbuminuria (>300 mg albumin/day) (Parving, 2004, personal communication EASD 2004). As many as 30% of people with newly diagnosed Type 2 diabetes will already have abnormally high urine albumin levels, three-quarters of whom will have microalbuminuria and the remainder overt diabetic nephropathy.16,17 The prevalence of microalbuminuria rises significantly with increasing age, duration of diabetes, and the co-existence of risk factors such as hypertension.18 Microalbuminuria clusters with the metabolic syndrome, and both conditions predict cardiovascular disease mortality.19 Indeed, since 1999 the World Health Organization (WHO) classification of metabolic syndrome has included urinary microalbuminuria as one component of the syndrome.20
There is abundant evidence that the occurrence of microalbuminuria in patients with hypertension or diabetes predicts adverse outcome. The LIFE (Losartan Intervention For Endpoint reduction in hypertension) study in high-risk hypertensives found that increased urinary albumin excretion is associated with left ventricular hypertrophy, abnormal geometry, and increased ventricular mass. The association was independent of blood pressure, diabetes, serum creatinine, age, or race, suggesting a close and direct correspondence between albuminuria and cardiac damage.21 In the Heart Outcomes Prevention Evaluation (HOPE) study, every 0.4 mg/mmol/L increase in albumin:creatinine ratio increased the adjusted hazard for major cardiovascular events by 5.9%.22 Recently, the Prevention of Renal and Vascular End-stage Disease (PREVEND) study demonstrated that fosinopril treatment vs. pravastatin significantly lowered urinary albumin excretion in patients with microalbuminuria and correspondingly was associated with a 40% (P=0.098) reduction in cardiovascular events.23 Although this study did not enable the beneficial effects of reduced blood pressure per se and RAAS-specific actions independent of blood pressure reduction to be distinguished, it is suggestive of a relationship between microalbuminuria and cardiovascular events.
Overall, the predictive power of microalbuminuria for major cardiovascular events and death has been estimated to be as great as that of being diagnosed with peripheral arterial disease using anklebrachial index.24
Screening
In the light of its emerging prognostic significance, regular screening for microalbuminuria has become a key priority for all patients with hypertension. Both the seventh report of the Joint National Committee and the European Society of HypertensionEuropean Society of Cardiology (ESHESC) guidelines recommend the routine evaluation of urinary albumin excretion rate as part of the assessment of target-organ damage.25,26 Indeed, some commentators have questioned whether these recommendations, and the criteria by which microalbuminuria are presently defined, are stringent enough. Levels of albumin excretion as low as 4.8 µg/min have been associated with an increased cardiovascular risk, suggesting that threshold levels for defining microalbuminuria should be revised downwards.8,27
Clinical and analytical variability has led to some uncertainties in some centres about the optimal method for detecting microalbuminuria, but its measurement is nevertheless moving from a tool of clinical research to one of clinical care. Several laboratory-based assays (such as radioimmunoassay and immunoturbidimetry) and near-patient tests have been developed to quantify trace amounts of albumin in urine and/or categorize patients into normo- or microalbuminuria, although there has been considerable variation in the performance of these diagnostic tests28 and accurate determination is only possible in the absence of infection, which should be excluded before measurement. Quantitative methods carried out on 24 h urine samples are more accurate than simpler quantitative or qualitative approaches but are impractical for routine practice. Urinary albumin levels can vary widely from sample to sample in the same patient, and microalbuminuria is usually, therefore, diagnosed on the basis of three positive testsalbumin:creatinine ratio, urinary albumin excretion rate, or a combination of both, over a 36-month period.29 Although microalbuminuria determination is yet to be fully standardized, current assessment methods are sufficiently robust and straightforward to warrant periodic assessment for all hypertension patients.
 |
From renoprotection to cardioprotection: the emerging role of RAAS blockade
|
---|
Since renal dysfunction is now known to be a core driver of cardiovascular pathology even at the earliest stages of hypertensive disease, interventions that delay or reverse the development of nephropathy should be integrated in the management of hypertension whenever microalbuminuria or frank proteinuria are detected. All agents that reduce systolic and diastolic blood pressures reduce albuminuria, but the most potent renoprotective drugs appear to be antihypertensive agents which block the RAAS. These agents selectively attenuate intra-glomerular pressure by promoting vasodilation of the glomerular efferent arterioles and favourably affect the regression remodelling and the improvement of endothelial function in resistance arterioles, particularly in patients with nephrosclerosis.30
A number of angiotensin converting enzyme (ACE) inhibitors and two angiotensin II receptor blockers (ARBs), irbesartan and losartan, have demonstrated renoprotective effects in major prospective trials.31,32 Other classes of agents also affect the RAAS, including calcium antagonists and beta blockers,33 although problems with tolerability are possible with some agents, particularly when combined. New classes of agents, such as renin inhibitors and selective aldosterone receptor antagonists, also have renoprotective potential, although these agents currently lack the support of large clinical trials data available for some ARBs and ACE-inhibitors.3436
Trials of renoprotection with ACE-inhibitors and ARBs
ACE-inhibitors and ARBs are currently the leading classes of antihypertensives that provide additional renoprotective properties. There is substantial evidence that ACE-inhibitors reduce proteinuria.37 In addition, more recently, ramipril and enalapril have been shown to reduce microalbuminuria by 24 and 12.5%, respectively, more than non-RAAS-targeted antihypertensives, in both diabetic and non-diabetic subjects.3840 In addition, a recent substudy of the Irbesartan in Diabetic Nephropathy Trial (IDNT) found that the renal benefits of antihypertensive therapy were greater with irbesartan than with amlodipine, as for the same proportional change in proteinuria, the reduction in risk for kidney failure was significantly greater in patients treated with irbesartan compared with those treated with amlodipine (P=0.048).41 ARBs theoretically provide the advantage of a more complete blockade of angiotensin II activity than ACE-inhibitors, a putative advantage which can be expected to have benefits not only within the kidney but elsewhere in the cardiovascular system. However, the relative merits of ACE-inhibitors and ARBs, with the exception of the superior tolerability of ARBs, have not been determined in prospective trials and remain keenly debated.42,43
The ARB, irbesartan, has been shown in a large, long-term, prospective, randomized trial to reduce the development of nephropathy in patients with microalbuminuria independently of its blood pressure-lowering effect.31 In this study of 590 hypertensive patients with microalbuminuria and Type 2 diabetes, treatment with irbesartan 300 mg was associated with a highly significant 70% relative risk reduction in the development of overt nephropathy (P<0.001) and normoalbuminuria was restored in significantly more patients receiving irbesartan 300 mg once daily compared with blood pressure control by other, non-RAAS-directed antihypertensives (34 vs. 24%; P=0.006). The renoprotective effect, characterized by a persistent reduction of urinary albumin excretion, was sustained 1 month after the withdrawal from high-dose irbesartan therapy. These data convincingly demonstrate that angiotensin receptor blockade with irbesartan has a renoprotective effect in hypertensive patients larger than that attributable to the decrease in blood pressure by itself.31
Irbesartan was also shown to reduce or normalize microalbuminuria in 34% of patients with diabetes and developing renal dysfunction in a second, smaller study including 64 hypertensive and 60 normotensive patients, confirming that irbesartan reduces microalbuminuria independently of its blood pressure lowering effects.44 Restoration of normal urine albumin levels has also been demonstrated by irbesartan. In IRMA II, the restoration of normoalbuminuria was achieved in 34% of 590 patients receiving irbesartan at a dose of 300 mg daily (P=0.006).31
Two further ARBs, valsartan and candesartan, have also been shown to reduce microalbuminuria, even in small studies of short duration.45,46 Although it is premature to conclude that all ARBs are renoprotective as a class effect, these results are consistent with the proposition that RAAS blockade is a critical strategy to treat microalbuminuria or delay its progression to proteinuria.
With regard to frank proteinuria, two ARBs, irbesartan and losartan, have been demonstrated in large, long-term trials to be renoprotectiveIDNT and the Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study (Figure 1).32,47 IDNT showed that irbesartan provided significantly more renoprotection than the calcium channel antagonist, amlodipine, despite equivalent reductions in blood pressure.32 Irbesartan 300 mg once daily reduced the relative risk of reaching the composite endpoint, a doubling of the baseline serum creatinine level, end-stage renal disease, or death, by 20% compared with placebo (P=0.02) and by 23% compared with amlodipine (P=0.006).32 In RENAAL, the use of losartan reduced the risk of a composite endpoint (doubling of baseline serum creatinine level, end-stage renal failure, or death) by 16% (P=0.02) in a population of 1513 diabetic patients with baseline proteinuria.47
Further studies will be needed to characterize the most appropriate renoprotective strategy using RAAS blockade across the spectrum from early to late-stage kidney disease. One important finding to emerge from the studies completed to date, however, is that blockade should be initiated from the first confirmation of microalbuminuria, and indeed possibly at lower urinary albumin excretion rates than are currently used to define this condition.
An unsolved issue is the optimal dose of treatment. Theoretically, total blockade of angiotensin II action should provide greater renoprotection and could be achieved using ultra-high dose ARB therapy or ARB/ACE-inhibitor dual therapy. Small studies are currently investigating whether increased renoprotection using these approaches can be achieved at very high doses.48 At present, however, the evidence from major long-term trials supports the use of the highest currently approved daily dose of agents with proven renoprotective properties in the management of hypertensive patients with microalbuminuria30 and proteinuria.32,47
Does renoprotection also protect the heart?
From a cardiological viewpoint, a critical question is the degree to which antihypertensive drugs that protect the kidney offer additional cardiovascular protection by virtue of their renoprotective properties. Studies of ARBs indicate that they have co-ordinated, parallel benefits that are independent of their effects on blood pressure, throughout the cardiovascular system, with benefits not only in the kidney but also in the heart and vasculature.4952 It is not possible to separate the degree to which these benefits are a result of improved renal function, or of local RAAS blockade within other organs and the vasculature, but it is likely that both mechanisms are important.
The parallel benefits of RAAS blockade with regard to nephropathy and congestive heart failure are clearly established in clinical trials. In IDNT, irbesartan treatment was shown to delay the development of nephropathy and correspondingly reduced the incidence of congestive heart failure by 28%.32 Similarly in RENAAL, there was a 32% decrease in the incidence of congestive heart failure in patients treated with losartan compared with placebo, despite equivalent blood pressure control achieved with other classes of agent in the control group.47
However, the predicted benefits of renoprotection in terms of long-term survival and morbidity have yet to be demonstrated. Most recent trials of RAAS blockade vs. other forms of antihypertensive therapy, including ALLHAT, CAMELOT, and VALUE, have not shown an advantage for the RAAS-directed agent vs. comparators in terms of long-term survival or composite endpoints of cardiovascular events and mortality.5355 Importantly, however, these studies did not investigate the response in terms of baseline or post-treatment microalbuminuria, and do not yield information on whether preventing progression of renal disease was associated with survival benefits. Moreover, they did not investigate responses beyond 5 years of baseline, whereas the benefits of protecting renal function from the earliest stages would be expected to require longer period to demonstrate. Confirmatory evidence on the survival benefits of renoprotective antihypertensives is therefore yet to emerge and this field is unlikely to be free of controversy until more definitive data becomes available.
In addition, although RAAS-directed therapy is likely to be a key component of therapy for most hypertensives with microalbuminuria or nephropathy, in many cases it is not likely to be the only antihypertensive treatment, but rather to be one key component of a dual or multi-drug approach targeting different cardiovascular parameters. For instance, IDNT demonstrated that the amlodipine and irbesartan groups did not differ in the overall incidence of cardiovascular events. Although there was a greater incidence of heart failure in the amlodipine group, there was also a non-significant lower incidence of myocardial infarction in these patients.32,56 These results imply that the combination of an RAAS-directed agent with one or more other classes of antihypertensives with complementary cardioprotective effects may be the most effective way of achieving optimal long-term outcomes with the drug classes currently at our disposal.
 |
Antihypertensive power and end-organ protection
|
---|
Although the reno-cardioprotective effects of RAAS blockade are, in part, mediated through non-blood pressure-related mechanisms, powerful, prompt, and sustained blood pressure control is also crucial in achieving protection against end-organ damage and adverse outcomes in hypertensive patients. Care should be taken to ensure that target blood pressures are reached promptly and maintained in patients treated with RAAS-directed agents. In this regard, valsartan was recently shown in the VALUE trial not to control blood pressure as rapidly as the comparator antihypertensive, amlodipine, with the consequence that valsartan's putative cardioprotective benefits were lower than anticipated.54 The study authors suggested that this was because amlodipine achieved more rapid blood pressure control than valsartan,54 although other anti-ischaemic effects of amlodipine55 may have played a role.
Several newer ARBs, including irbesartan, candesartan, telmisartan, and olmesartan have been shown to be more potent antihypertensive agents than valsartan or losartan.5762 In addition, irbesartan was shown both in a specific comparative study and in the long-term IDNT study to be as potent as amlodipine in reducing blood pressure.32,63 The addition of other agents, notably hydrochlorothiazide in fixed combinations, also bolsters the antihypertensive efficacy of RAAS-directed agents, providing what is likely to be the strategy of choice for most patients.
 |
Conclusions
|
---|
It is now clear that renal dysfunction is intimately associated with cardiovascular disease from its earliest stages through to end-organ failure. Accordingly, the assessment and treatment of renal function has become a central consideration for cardiologists in the management of even mild to moderate hypertension and diabetes patients.
The first major consequence of this development is in clinical evaluation and risk assessment. In accordance with the seventh report of the Joint National Committee and the ESHESC guidelines,25,26 the urinary albumin excretion rate should now be routinely assessed in patients with hypertension.
The second major consequence is in medical management. A case now exists for using antihypertensive drugs with proven renoprotective properties in all patients with hypertension or diabetes who have microalbuminuria or proteinuria. Such a strategy would be expected not only to protect the kidneys against further deterioration, but also to protect against progression of systemic cardiovascular disease, both by reducing the deleterious repercussions of renal dysfunction, and by protecting endothelial function elsewhere in the body. However, long-term data from appropriately designed clinical trials are not yet available to confirm the reno-cardioprotective effects of RAAS blockade in terms of hard survival endpoints, and the results of several completed trials suggest that combining of RAAS-directed therapy with other classes of agents that are cardioprotective through different mechanisms may represent the most appropriate antihypertensive strategy for many patients.
In addition, the need for renoprotection should not overshadow the crucial importance of blood pressure control. The protective effects of RAAS blockade against end-organ dysfunction must be complemented by powerful, early blood pressure control if maximum benefits to the patient are to be achieved. Newer ARBs such as irbesartan, telmisartan, and olmesartan are more potent than the older ARBs, losartan and valsartan, though hydrochlorothiazide fixed combinations are now available for most ARBs, and provide additive benefits in blood pressure reduction.
In conclusion, renal considerations now have a central role to play in the assessment and management of hypertension from its earliest stages. For patients with incipient or frank renal dysfunction, an aggressive approach to hypertension management, combining rapid blood pressure control with proven renoprotection, is likely to become integral to therapeutic strategy targeting long-term cardioprotection.
 |
Acknowledgements
|
---|
We thank the reviewer for helpful comments on an earlier version of this paper.
 |
References
|
---|
- Dumaine R, Collet J-P, Tanguy M-L, Mansencal N, Dubios-Randé J-L, Henry P, Steg PG, Michel P-L, Allouch P, Cohen A, Colin P, Durand E, Montalescot G; SYCOMORE Investigators. Prognostic significance if renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study). Am J Hypertens 2004;94:15431547.
- Silverberg D, Wexler D, Blum M, Schwartz D, Iaina A. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens 2004;13:163170.[ISI][Medline]
- Vashist A, Heller EN, Brown EJ Jr, Alhaddad IA. Renal artery stenosis: a cardiovascular perspective. Am Heart J 2002;143:559564.[CrossRef][ISI][Medline]
- Weir MR, Dzau VJ. The reninangiotensinaldosterone system: a specific target for hypertension management. Am J Hypertens 1999;12:205S213S.[ISI][Medline]
- Strawn WB, Ferrario CM. Mechanisms linking angiotensin II and atherogenesis. Curr Opin Lipidol 2002;13:505512.[CrossRef][ISI][Medline]
- Schiffrin EL. Canadian Institutes of Health Research (CIHR) Multidisciplinary Research Group on Hypertension. Beyond blood pressure: the endothelium and atherosclerosis progression. Am J Hypertens 2002;15:115S122S.[CrossRef][ISI][Medline]
- Ferrario CM, Richmond RS, Smith R, Levy P, Strawn WB, Kivlighn S. Reninangiotensin system as a therapeutic target in managing atherosclerosis. Am J Ther 2004;11:4453.[CrossRef][Medline]
- Volpe M, Cosentino F, Ruilope LM. Is it time to measure microalbuminuria in hypertension? J Hypertens 2003;21:12131220.[CrossRef][ISI][Medline]
- De Gaudio AR, Adembri C, Grechi S, Novelli GP. Microalbuminuria as an early index of impairment of glomerular permeability in postoperative septic patients. Intensive Care Med 2000;26:13641368.[CrossRef][ISI][Medline]
- Diercks GF, van Boven AJ, Hillege HL, Janssen WM, Kors JA, de Jong PE, Grobbee DE, Crijns HJ, van Gilst WH. Microalbuminuria is independently associated with ischemic electrocardiographic abnormalities in a large non-diabetic population: the PREVEND (Prevention of REnal and Vascular ENdstage Disease) study. Eur Heart J 2000;21:19221927.[Abstract/Free Full Text]
- Haffner SM, Stern MP, Gruber MK, Hazuda HP, Mitchell BD, Patterson JK. Microalbuminuria: potential marker for increased cardiovascular risk factors in nondiabetic subjects? Arteriosclerosis 1990;10:727731.[Abstract/Free Full Text]
- Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia 1999;42:263285.[CrossRef][ISI][Medline]
- Fioretto P, Stehouwer CD, Mauer M, Chiesura-Corona M, Brocco E, Carraro A, Bortoloso E, van Hinshenberg V, Crepaldi G, Nosadini R. Heterogeneous nature of microalbuminuria in NIDDM: studies of endothelial function and renal structure. Diabetologia 1998;41:233236.[CrossRef][ISI][Medline]
- Leoncini G, Sacchi G, Viazzi F, Ravera M, Parodi D, Ratto E, Vettoretti S, Tomolillo C, Deferrari G, Pontremoli R. Microalbuminuria identifies overall cardiovascular risk in essential hypertension: an artificial neural network-based approach. J Hypertens 2002;20:13151321.[CrossRef][ISI][Medline]
- Knight EL, Kramer HM, Curhan GC. High-normal blood pressure and microalbuminuria. Am J Kidney Dis 2003;41:588595.[CrossRef][ISI][Medline]
- Esmatjes E, Castell C, Gonzalez T, Tresserras R, Lloveras G; The Catalan Diabetic Nephropathy Study Group. Epidemiology of renal involvement in type II diabetics (NIDDM) in Catalonia. Diabetes Res Clin Pract 1996;32:157163.[CrossRef][ISI][Medline]
- Passa P, Chatellier G; Diab-Hycar Study Group. The Diab-Hycar Study. Diabetologia 1996;39:16621667.[CrossRef][ISI][Medline]
- Delcourt C, Vauzelle-Kervroedan F, Cathelineau G, Papoz L; CODIAB-INSERM-ZENECA Pharma Study Group. Low prevalence of long-term complications in non-insulin-dependent diabetes mellitus in France: a multicenter study. J Diabetes Complicat 1998;12:8895.[CrossRef][ISI][Medline]
- Lane JT. Microalbuminuria as a marker of cardiovascular and renal risk in type 2 diabetes mellitus: a temporal perspective. Am J Physiol Renal Physiol 2004;286:442450.[CrossRef]
- World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Department of Noncommunicable Disease Surveillance, Geneva, 1999.
- Olsen MH, Wachtell K, Hermann KL, Bella JN, Dige-Petersen H, Rokkedal J, Ibsen H. A blood pressure independent association between glomerular albumin leakage and electrocardiographic left ventricular hypertrophy: the LIFE study. J Hum Hypertens 2002;16:591595.[CrossRef][ISI][Medline]
- Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421426.[Abstract/Free Full Text]
- Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004;110:28092816.[Abstract/Free Full Text]
- Jager A, Kostense PJ, Ruhe HG, Heine RJ, Nijpels G, Dekker JM, Bouter LM, Stehouwer CD. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Arterioscler Thromb Vasc Biol 1999;19:617624.[Abstract/Free Full Text]
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:12061252.[Abstract/Free Full Text]
- De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger Cats V, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D; Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003;24:16011610.[Free Full Text]
- Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H, Appleyard M, Jensen JS. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation 2004;110:3235.[Abstract/Free Full Text]
- Donnelly S, Rae R. Microalbuminuria: how informative and reliable are individual measurements? J Hypertens 2003;21:12291233.[CrossRef][ISI][Medline]
- Bennett PH, Haffner S, Kasiske BL, Keane WF, Mogensen CE, Parving HH, Steffes MW, Striker GE. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995;25:107112.[ISI][Medline]
- Ruilope LM. What is the impact of PRIME on real-life diabetic nephropathy? Int J Clin Pract 2004;58:268276.[CrossRef][ISI][Medline]
- Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870878.[Abstract/Free Full Text]
- Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851860.[Abstract/Free Full Text]
- Holmer SR, Hense HW, Danser AH, Mayer B, Riegger GA, Schunkert H. Beta adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics. Heart 1998;80:4548.[Abstract/Free Full Text]
- Davis K, Nappi J. The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist. Clin Ther 2003;25:26472668.[CrossRef][ISI][Medline]
- Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, Ravid M. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study. Diabet Med 2004;21:471475.[CrossRef][ISI][Medline]
- Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:19.[CrossRef][Medline]
- Keilani T, Schlueter W, Batlle D. Selected aspects of ACE inhibitor therapy for patients with renal disease: impact on proteinuria, lipids and potassium. J Clin Pharmacol 1995;35:8797.[Abstract/Free Full Text]
- Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253259.[CrossRef][ISI][Medline]
- Monster TB, Janssen WM, de Jong PE, de Jong-van den Berg LT; PREVEND Study Group. The impact of antihypertensive drug groups on urinary albumin excretion in a non-diabetic population. Br J Clin Pharmacol 2002;53:3136.[CrossRef][ISI][Medline]
- Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1998;128:982988.[Abstract/Free Full Text]
- Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB, Lewis EJ. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes and overt nephropathy. Am J Kidney Dis 2005;45:282287.
- Ball SG, White WB. Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockersa gap in evidence-based medicine. Am J Cardiol 2003;91(Suppl.):15G21G.[ISI][Medline]
- Ruilope LM, Segura J, Schiffrin EL. ACE inhibition or angiotensin receptor blockade: which should we use in diabetic patients? J Renin Angiotensin Aldosterone Syst 2003;4:7479.[ISI][Medline]
- Sasso FC, Carbonara O, Persico M, Iafusco D, Salvatore T, D'Ambrosio R, Torella R, Cozzolino D. Irbesartan reduces the albumin excretion rate in microalbuminuric type 2 diabetic patients independently of hypertension: a randomized double-blind placebo-controlled crossover study. Diabetes Care 2002;25:19091913.[Abstract/Free Full Text]
- Morgan T, Anderson A, Bertram D, MacInnis RJ. Effect of candesartan and lisinopril alone and in combination on blood pressure and microalbuminuria. J Renin Angiotensin Aldosterone Syst 2004;5:6471.[ISI][Medline]
- Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106:672678.[Abstract/Free Full Text]
- Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861869.[Abstract/Free Full Text]
- Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving HH. Dual blockade of the reninangiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 2003;63:18741880.[CrossRef][ISI][Medline]
- Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME, Jandeleit-Dahm KA. Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis. Circulation 2004;109:15361542.[Abstract/Free Full Text]
- Dählof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:9951003.[CrossRef][ISI][Medline]
- Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875886.[CrossRef][ISI][Medline]
- Malmqvist K, Kahan T, Edner M, Held C, Hagg A, Lind L, Muller-Brunotte R, Nystrom F, Ohman KP, Osbakken MD, Ostergern J. Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 2001;19:11671176.[CrossRef][ISI][Medline]
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk antihypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:29812997.[Abstract/Free Full Text]
- Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group. VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:20222031.[CrossRef][ISI][Medline]
- Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ; CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary artery disease and normal blood pressure. The CAMELOT Study: a randomized controlled trial. JAMA 2004;292:22172226.[Abstract/Free Full Text]
- Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, Drury PL, Esmatjes E, Hricik D, Parikh CR, Raz I, Vanhille P, Wiegmann TB, Wolfe BM, Locatelli F, Goldhaber SZ, Lewis EJ; Irbesartan Diabetic Nephropathy Trial. Collaborative Study Group. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138:542549.[Abstract/Free Full Text]
- Deedwania PC, Amlodipine Study Group. Anti-ischemic effects of amlodipine in patients with stable angina pectoris and myocardial ischemia during daily life. Am J Cardiol 1999;83:11171119.[CrossRef][ISI][Medline]
- Mancia G, Korlipara K, van Rossum P, Villa G, Silvert B. An ambulatory blood pressure monitoring study of the comparative antihypertensive efficacy of two angiotensin II receptor antagonists, irbesartan and valsartan. Blood Press Monit 2002;7:135142.[CrossRef][ISI][Medline]
- Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. Irbesartan/Losartan Study Investigators. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Am J Hypertens 1998;11:445453.[CrossRef][ISI][Medline]
- Bakris G, Gradman A, Reif M, Wofford M, Munger M, Harris S, Vendetti J, Michelson EL, Wang R. CLAIM Study Investigators. Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. J Clin Hypertens 2001;3:1621.
- Lacourciere Y, Krzesinski JM, White WB, Davidai G, Schumacher H. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004;9:203210.[CrossRef][ISI][Medline]
- Ball KJ, Williams PA, Stumpe KO. Relative efficacy of an angiotensin II antagonist compared with other antihypertensive agents: olmesartan medoxomil versus antihypertensives. J Hypertens 2001;19(Suppl. 1):S49S56.
- Neutel J, Germino W, Smith D. The antihypertensive efficacy and safety of irbesartan compared with amlodipine for the treatment of mild-to-moderate hypertension. (Abstract no. D068). Am J Hypertens 1999;12:128A.