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Angiotensin Receptor Blockers: RAAS Blockade and Renoprotection

Posted on: Friday, 27 June 2008, 06:01 CDT

By Ruilope, Luis M

Key words: Angiotensin receptor blockers - Kidney disease - Renin- angiotensin-aldosterone system - Renoprotection ABSTRACT

Introduction: Chronic kidney disease (CKD) is an increasingly prevalent public health concern and is associated with a high risk of adverse cardiovascular outcomes. Renal impairment is frequently associated with hypertension and there is compelling evidence of the benefits of antihypertensive therapy for reducing progression of kidney disease. The central role of the reninangiotensin- aldosterone system (RAAS) in hypertension and renal disease has led to interest in the ability of RAAS-blocking agents to provide benefits beyond blood pressure control.

Scope: This review explores the mechanisms involved in CKD development, assesses markers of CKD progression, explores the role of the RAAS in renal disease, and examines RAAS blockade as a therapeutic option for renoprotection. For this purpose, a non- systematic literature review was conducted using the Medline database.

Findings: Studies in patients with diabetic renal disease have shown that RAAS blockade with angiotensin converting enzyme (ACE)- inhibitors or angiotensin receptor blockers (ARBs) reduces progression of renal disease. Similarly, several studies have demonstrated the benefits of ACE inhibitors in non-diabetic renal disease, although few studies have been conducted with ARBs in this setting. At present, there is little evidence to determine the relative merits of ARBs and ACE inhibitors in terms of clinical outcomes, although ARBs appear to have advantages in terms of renal haemodynamics and measures of renal function.

Conclusions: The beneficial effects of ARBs, which result from a combination of antihypertensive, haemodynamic, antiproteinuric and pleiotropic mechanisms, provide a strong rationale for considering the use of these agents in the treatment of high-risk patients.

Introduction

Chronic kidney disease (CKD), the progressive permanent loss of kidney function, is defined by the National Kidney Foundation (NKF) according to the presence of kidney damage (structural or functional abnormalities manifested by markers of pathological abnormalities) or the level of kidney function (glomerular filtration rate [GFR] <60ml/min/1.73m^sup 2^ for at least 3 months)1. Normal GFR approximates 120ml/min and CKD is classified in five sequential stages reflecting the progressive nature of the condition, from a mild decrease in kidney function (stages 1 and 2; GFR 60-90 ml/min) to kidney failure (stage 5; GFR < 15ml/min). Chronic renal failure or end-stage renal disease (ESRD) without renal replacement therapy could potentially lead to death.

CKD is a major public health concern worldwide2, and its prevalence is increasing by approximately 8% per year3. The primary causes differ by region, age, gender and race, with diabetic nephropathy the most common underlying cause in Europe, the US and Japan (reflecting the age-related increase in metabolic disease in the industrialised world), and chronic glomerulonephritis or systemic hypertension in developing countries4. The progressive nature of hypertensive renal disease, despite therapy, and a failure to reduce blood pressure (BP) to a level where damage does not occur also contribute to the increasing prevalence.

CKD is associated with an increase in adverse cardiovascular (CV) outcomes. Indeed, patients with CKD are much more likely to die of CV disease than ESRD5. For example, young dialysis patients have approximately 500-fold increased CV disease mortality rates compared with the general population6. With the high morbidity and mortality rates associated with CKD, preventing disease progression is important. The interrelationship between CKD and CV disease is complex, with several common mediating mechanisms and co- facilitatory roles. This review examines this interrelationship by evaluating current knowledge on the mechanisms involved in CKD development, assessing markers for CKD progression, exploring the role of the renin-angiotensin-aldosterone system (RAAS) in renal disease, and examining RAAS blockade as a therapeutic option for renoprotection. For this paper, a non-systematic literature review was conducted during July 2007 using the Medline database (it is acknowledged that the use of a single database may not have fully captured all the available literature/ data available at the time of conducting the search). The review included evaluation of mechanistic studies, epidemiological studies, clinical trials, outcomes studies, and meta-analyses.

Assessing renal status

Renal status is most accurately assessed by GFR measurement, with lower values indicative of a more advanced disease stage, as defined by the NKF1. As GFR cannot be measured directly, urinary excretion of inulin is the gold standard technique for estimating GFR. However, since intravenous infusion and timed urine collections make inulin clearance unwieldy, estimates based on serum creatinine concentration are the most widely used indices of renal function in clinical practice1,7. Creatinine, the metabolite of creatine in muscle tissue, is produced at a relatively steady rate with standard diet and normal physical activity, so renal excretion should be constant with only slight variations between individuals by age and sex due to differences in muscle mass. Despite its wide use, there are limitations associated with serum creatinine as a surrogate marker of GFR, including methodological interference in its assessment, issues of extra-renal elimination and metabolic variation between patients, all of which can contribute to a lack of sensitivity1,7. For example, patients with a reduced GFR (40 ml/min/ 1.73(2)) were found to have serum creatinine within the normal range8. Although they provide a simple and cheap laboratory measure and are frequently used in clinical trials, serum creatinine levels should not be relied on as a sole assessment of kidney function in clinical practice9. Given the lack of sensitivity of serum creatinine as a marker, a doubling (100% increase) of serum creatinine should be used in preference to a 50% increase in estimated GFR, and this is the measure used routinely in clinical studies to provide an index of renal function. This is a very specific measure because, unless there is a change in diet, a doubling of serum creatinine reflects a true decline in renal function7. The accepted rule of thumb is that a doubling of serum creatinine is equivalent to a 50% reduction in GFR10. A transforming equation, such as the Modification of Diet in Renal Disease (MDRD) Study equation, can be used to estimate GFR from serum creatinine concentration. This equation forms the basis of the widely used GFR calculator (adult and paediatric versions) and minimises some of the limitations of using serum creatinine levels in isolation1.

Renal function as a predictor of CV outcomes

Depressed GFR has been shown to be predictive of CV outcomes including heart failure and death (Figure 1)11. A longitudinal study involving more than 1 million patients assessed over a median follow- up period of 2.84 years revealed that the adjusted risks of death and CV events increased with decreasing GFR. The adjusted hazard ratios (HR) for death were 1.2, 1.8, 3.2 and 5.9 for GFRs of 45-59, 30-44, 15-29 and < 15 ml/min/1.73 m^sup 2^, respectively, while the corresponding adjusted risks of CV events were 1.4, 2.0, 2.8 and 3.4, respectively11.

Predictive value of creatinine

The Hypertension Detection and Follow-up Program trial12 and the Hypertension Optimal Treatment Trial13 are examples showing that serum creatinine is an excellent predictor of increased CV risk and mortality. Delaying the time to doubling of serum creatinine has been shown to be predictive of a delay in ESRD14. An analysis of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial has compared the usefulness of estimated creatinine clearance (Cockroft-Gault) and estimated GFR (MDRD) as predictors of CV outcome15. While creatinine clearance provided a significant prediction of the risk of all-cause death, GFR was found to be more informative than creatinine clearance as a predictor of CV outcomes, providing significant predictions for composite cardiac mortality and morbidity, myocardial infarction, congestive heart failure and all-cause mortality.

Figure 1. Association between glomerular filtration rate (GFR) and cardiovascular events. Reproduced with kind permission from Go et al. N Engl J Med 2004;351:1296-30511. Copyright (c) 2004 Massachusetts Medical Society. All rights reserved.

Predictive value of proteinuria

Early-stage proteinuria may also be an early and sensitive marker of kidney disease. It is usually measured as urinary albumin concentration (24-hour excretion <30, 30-300 or > 300 mg/day, in adults for normoalbuminuria, microalbuminuria and macroalbuminuria, respectively; or spot concentrations of > 3 mg/dl) or total urinary protein (24-hour excretion of > 300 mg/day, or spot concentration of > 30 mg/dl in adults)1. Elevated urinary albuminxreatinine or proteinxreatinine ratios are also used as indicators of kidney disease, although these are subject to diurnal, age and gender differences. In a study of 5545 adults, the adjusted risk of major CV events increased by 5.9% for every 0.4 mg/mmol increase in baseline urine albumin : creatinine ratio. Increased risk started well below the minimum value indicated by the NKF for microalbuminuria, showing that CV risk is elevated even in patients with mild renal disease16. These data supported the findings of an earlier study in 2762 adults, which showed increased risk of coronary heart disease and death in patients with urinary albumin excretion above the upper quartile (>4.8 [mu]g/min)17. Importance of BP lowering in patients with decreased renal function

Hypertension can be a cause, a complication and a result of CKD, and has been identified as a key modifiable risk factor in patients with decreased renal function. In addition to hypertension, other factors contribute to the pathophysiology of CKD, including smoking and metabolic disorders. Primary hypertension can lead to CKD due to endothelial injury from local and systemic inflammatory mediators and haemodynamic shear injury. This injury is an important step in the development of vasculopathy, causing nephron ischaemia with nephrosclerosis18.

The benefits of strict BP control in slowing kidney disease progression have been demonstrated in several clinical trials19. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a target BP < 130/80 mmHg in patients with CKD20. Guidelines from the European Society of Hypertension/European Society of Cardiology (ESH/ ESC) also recommend a BP < 130/80 mmHg to protect against progression of renal dysfunction, and to at least 120/80 mmHg when proteinuria is greater than 1 g/day21.

Questions regarding the choice of antihypertensive agent in patients with renal dysfunction and whether specific agents provide renoprotective benefits beyond BP lowering are of interest and will be examined in the remainder of this review.

Role of RAAS activation in renal disease

The RAAS regulates BP and is a key factor in targetorgan damage development. It regulates renal vasomotor activity and maintains optimal salt and water homeostasis through coordinated effects on the heart, blood vessels and kidney. Pathological consequences such as renal dysfunction can result from overactivity of this cascade22.

Angiotensin II, an effector molecule of the RAAS, has complex, multifaceted effects on renal dynamics that can lead to renal damage and loss of function (Figure 2). Although all highly interrelated, the effects of angiotensin II in renal disease can be divided into haemodynamic, proteinuric and pleiotropic mechanisms.

Haemodynamic effects

An activated RAAS promotes both systemic and glomerular capillary hypertension, which can induce haemodynamic injury to the vascular endothelium and glomerulus directly though shear stress. Consequently, the kidneys lose their ability to regulate glomerular filtration flow and pressure, with resultant hyperfiltration, manifested as albuminuria and proteinuria. When the proximal convoluted tubule reabsorbs the excess protein, secretion of vasoactive substances damage the glomerular tubular apparatus. Nephron damage further activates the RAAS, resulting in increased sympathetic tone and fluid overload, compounding the progression of hypertension (and increasing nephron loss)23. This leads to an axis of amplification between hypertension and renal dysfunction, whereby 90% of patients with ESRD have hypertension24 and 18% of patients with untreated hypertension ultimately develop ESRD25.

Figure 2. Role of angiotensin II in chronic renal disease. Figure reproduced with kind permission from www. hypenensiononline.org (Accessed July 2007). CTGF, connective tissue growth factor; GFR, glomerular filtration rate; NF-kappaB, nuclear factor-kappa B; PAI- 1, plasminogen activator inhibitor-1; TGF-kappa, transforming growth factor-beta

Angiotensin II also has a direct haemodynamic effect on the kidney, acting at the afferent, but mainly the efferent, arterioles of the glomerulus, leading to an increased intraglomerular pressure26. This excess pressure can lead to microalbuminuria. Angiotensin II may therefore cause pressure-induced renal injury via its ability to induce systemic and glomerular hypertension and cause ischaemia-induced renal injury secondary to angiotensin-induced proteinuria.

Proteinuric effects

Proteinuria is an important factor in the progression of kidney disease27. Angiotensin II may contribute to its pathogenesis by increasing glomerular permeability to macromolecules28. Additionally, leakage of serum proteins increases the protein load in proximal tubules thereby promoting inflammation and transformation of tubular cells to myofibroblasts, with resultant tubulointerstitial injury29.

Pleiotropic effects

Angiotensin II also has other, non-haemodynamic, pleiotropic effects that can cause renal injury. It stimulates the synthesis of extracellular matrix proteins by means of the profibrotic cytokine transforming growth factor-beta, induces oxidative stress, stimulates chemokines and osteopontin that may cause local inflammation, and stimulates vascular and mesangial cell proliferation and hypertrophy30. Moreover, angiotensin II stimulates plasminogen activator inhibitor-1 production by endothelial and smooth muscle cells, activates macrophages and increases phagocytosis and adrenal production of aldosterone28. Together, these non-haemodynamic effects lead to structural changes within the kidney that accelerate the damage caused by haemodynamic and proteinuric effects.

RAAS blockade and renoprotection

Mechanisms

The various roles of angiotensin II on the kidney and systemic BP suggest that RAAS blockade should offer renoprotective benefits by decreasing intraglomerular pressure, minimising the stressors on the nephron and reducing proteinuria23. Blockade should also mitigate the pleiotropic effects of RAAS activation, preventing the inflammation and cellular proliferation that contribute to organ damage31. In a study of 96 patients with type 2 diabetes, hypertension, a GFR > 80 ml/min, and normo- or microalbuminuria, RAAS blockade (with telmisartan or ramipril) improved renal endothelial function, which may help to preserve CV and renal function32.

Other CKD risk factors

In addition to BP lowering, good glycaemic control, lipid lowering with statin therapy and smoking cessation have been shown to be associated with attenuation of renal disease progression33. Whether the benefits of these strategies are additive to the effects of RAAS blockade remains speculative. However, in a study of patients with proteinuria, CKD and hypercholesterolaemia, and receiving treatment with a RAAS blocker (angiotensin-converting enzyme inhibitor [ACEI] or angiotensin receptor blocker [ARB]) plus atorvastatin, the benefits seen in terms of reduced proteinuria and rate of decline of renal function were considered to be additive34.

Clinical evidence for renoprotection

In patients with advanced nephropathy and hypertension, the heightened risk of complications is such that BP lowering alone is sufficient to provide a significant improvement in renal function and outcomes, and any additional protective benefits from RAAS blockade are less relevant. It is in those whose renal impairment is less severe that the protective effects of RAAS blockade over and above BP lowering have a significant impact, and intervention at this stage can provide benefits in terms of slowing kidney disease progression35. Thus, a priority should be placed on early detection of hypertensive nephrosclerosis via detection of microalbuminuria and initiating therapy to prevent ESRD progression.

Diabetic renal disease

With the epidemic of metabolic disease and an ageing population, diabetes is increasingly becoming the most common cause of renal disease worldwide4. The natural history of diabetic nephropathy is characterised by the onset of microalbuminuria, hypertension, declining GFR and development of nephrotic syndrome over many years1. International guidelines such as the Kidney Disease Outcomes Quality Initiative, ESH/ESC and JNC 7 recommend RAAS blockers for patients with hypertension and diabetic kidney disease (and non- diabetic kidney diseases with proteinuria) and ARBs specifically in patients with type 2 diabetes and nephropathy1,20,21. ESH/ESC recommends that, in microalbuminuric patients, antihypertensive therapy should preferably include an RAAS-blocking agent and should be initiated when BP is in the high-normal range (130-139/85-89 mmHg)21.

Table 1. Angiotensin II receptor blockade in diabetic renal disease

Several large-scale studies have demonstrated the unequivocal benefits of RAAS blockade through the use of ARBs and ACEIs in patients with diabetic nephropathy.

Angiotensin II receptor blockade

Table 1 provides a brief summary of various trials evaluating ARBs in diabetic renal disease. The Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study showed that when compared with placebo, addition of losartan to standard antihypertensive therapy reduced the risk of progression of nephropathy by 25% (p = 0.006)36. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), doubling of serum creatinine was reduced by 37% with irbesartan compared with amlodipine (p < 0.001) and by 33% compared with placebo (p = 0.003)37. At 12 months, irbesartan had decreased the incidence of proteinuria by 41 % (compared with 11 % and 16% with amlodipine and placebo, respectively). Additionally, irbesartan 150mg and 300 mg reduced progression to clinical microalbuminuria by 39% and 70% compared with placebo in the IRbesartan in patients with type II diabetes and MicroAlbuminuria study (IRMA-II)38. Regression to normoalbuminuria occurred in 34% of patients receiving irbesartan 300 mg and 21% of patients in the placebo group (p = 0.006). The treatment effect of irbesartan was not altered when the data were adjusted for BP levels, indicating effects independent of BP lowering.

In the MicroAlbuminuria Reduction with VALsartan (MARVAL) study, valsartan was compared with amlodipine in hypertensive and normotensive patients with type 2 diabetes and microalburninuria39. At the end of the 24-week treatment period, the mean urinary albumin excretion rate (UAER) in valsartan-treated patients was reduced by 44% (p < 0.001) versus baseline, compared with 8% versus baseline for amlodipine (p = NS vs. baseline; p < 0.001 valsartan vs. amlodipine). Significantly (p < 0.001) more patients reverted to normoalbuminuria (UAER < 20 [mu]g/min) with valsartan (30%) than with amlodipine (14.5%). BP reductions were similar in both groups, suggesting that the antiproteinuric effect of valsartan was independent of BP lowering39. The ongoing Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study was designed to evaluate whether the development of microalbuminuria in patients with type 2 diabetes can be slowed or prevented by treatment with olmesartan40. ROADMAP will also assess the effects of olmesartan on fatal and non-fatal CV events, to show whether prevention/delay of microalbuminuria onset will translate into protection against both CV and renal disease.

The optimal dose of ARBs for renoprotection is unknown and suboptimal dosing may be responsible for the development and progression of diabetic renal disease in some patients. Evidence from studies such as IRMA-II38 suggests that additional renoprotective benefits might be provided by doses higher than those indicated for BP lowering.

The Diovan Reduction Of Proteinuria (DROP) trial investigated the effects of high-dose valsartan (up to 640 mg) on proteinuria in patients with hypertension, type 2 diabetes and microalbuminuria41. At doses of 160 mg, 320 mg and 640 mg, valsartan reduced UAER by up to 48%, with reductions up to 65% in patients who achieved target BP control of < 130/80 mmHg. Normalisation of UAER (< 20 [mu]g/min) with these doses was achieved by 12.4%, 19.2% and 24.3% of patients, respectively, after 30 weeks of treatment. All three doses of valsartan were well tolerated with slightly more frequent dizziness and headache with the 640 mg dose.

Renoprotective effects of high-dose ARB therapy were also investigated in a study evaluating 2 months' treatment with irbesartan in 52 patients with hypertension, type 2 diabetes and microalbuminuria42. UAER was reduced by 52%, 49% and 63% from baseline in patients receiving irbesartan 300 mg, 600 mg and 900 mg, respectively. Increasing doses did not have any significant effects on ambulatory BP and the renoprotective effect was also shown to be independent of GFR. Higher-dose irbesartan was generally well- tolerated, with mild and transient dizziness the most frequently reported adverse event.

Additional studies to determine the plateau of the dose-response curve of ARBs with respect to renoprotection are warranted.

Angiotensin converting enzyme inhibition

Reduction of microalbuminuria using an ACEI in patients with hypertension, type 2 diabetes and microalbuminuria was examined in the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT)43. After 3 years of treatment, the incidence of persistent microalbuminuria was lower in patients receiving trandolapril plus verapamil (5.7%) and in patients receiving trandolapril alone (6.0%) than in patients receiving verapamil alone (11.9%) or placebo (10%).

The Diabetic Exposed to Telmisartan And Enalapril study (DETAIL), one of the few trials comparing the renoprotective benefits of ACEIs and ARBs in type 2 diabetics with early nephropathy, showed that telmisartan was non-inferior to enalapril, supporting the clinical equivalence of ACEIs and ARBs with respect to renoprotection44. However, given that these data were in patients with early nephropathy, they may not be applicable across all patient populations.

Although the BENEDICT and DETAIL studies could both be considered as supporting the selection of an ACEI as the first-choice treatment for patients with type 2 diabetes and early renal damage, several issues should be considered. In the BENEDICT study, BP control failed to achieve the standard recognised in clinical guidelines. Better BP control could therefore have improved the protective capacity of RAAS inhibition. In addition, 46% of patients also received a sympathetic nervous system blocker during the study43, which could have had a positive influence on albuminuria45 and might have enhanced the beneficial effect of the ACEI. Also in this study, the percentage of patients becoming microalbuminuric was above the 2% per year considered usual (UKPDS46) among diabetic patients. In the DETAIL study44, the use of low doses of telmisartan (40 mg) in some patients could have obscured the existence of potential differences between the treatments.

Non-diabetic kidney disease

Non-diabetic kidney diseases include glomerular diseases, vascular diseases other than renal artery disease, tubulointerstitial disease and cystic disease. In a meta-analysis of 11 randomised trials in patients with non-diabetic renal disease, ACEI-based regimens were more effective at slowing renal disease progression than antihypertensive regimens without ACEIs, even after adjustment for the greater reductions in BP seen with ACEI-based therapy47. Lowering BP to a 'low' goal of 128/78 mmHg in the African American Study of Kidney disease and hypertension trial (AASK) had no impact on the rate of progression of renal dysfunction in African American patients with hypertension and nephrosclerosis48. However, the risk of the composite primary endpoint (rate of change in GFR) was reduced by 22% with the ACEI ramipril compared with metoprolol and by 38% compared with amlodipine. These reductions suggest that the choice of agent for slowing progression of renal dysfunction may be more important than for BP lowering in non-diabetic renal disease.

Findings from a prospective observational cohort study in patients with peripheral arterial disease have also shown that the use of an ACEI was associated with improved renal and CV outcomes49. Chronic use of ACEIs was associated with a HR of 0.74 for ESRD and 0.84 for mortality.

Few studies have been performed with ARBs in non-diabetic renal disease. Results from the Japanese COOPERATE study showed that ARBs and ACEIs had similar effects in reducing proteinuria and slowing renal disease progression, and that combination therapy with the two agents was superior to monotherapy with either agent alone50.

Meta-analysis of RAAS inhibition and renal outcomes

Casas and colleagues performed a meta-analysis of antihypertensive drugs and progression to renal disease that included both primary dichotomous endpoints (doubling of creatinine and ESRD) and secondary continuous markers of renal outcomes (creatinine, albuminuria and GFR)51. Comparisons of RAAS blockers (ACEIs and ARBs) with other antihypertensive agents showed a relative risk of 0.71 for doubling of creatinine and 0.87 for benefit on ESRD. When only including studies in patients with diabetic nephropathy, the corresponding relative risks were 1.09 and 0.89. The authors suggested that the renoprotective benefits demonstrated with RAAS inhibition probably derived solely from a BP- lowering effect51. However, a different conclusion might have been drawn had the meta-analysis focused on trials primarily concerned with renal disease rather than also including studies mainly concerned with CV disease. Several of the studies that did not focus primarily on renal disease had relatively short follow-up durations or employed low ACEI or ARB doses52. In particular, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) accounted for 90% of the ACEI data within the meta-analysis, was not primarily designed to assess renal outcomes, did not measure proteinuria, and employed an ACEI that was sub- optimal for renoprotection. While the meta-analysis indicates that the doses routinely employed to treat hypertension provide renoprotection consistent with BP reductions, higher doses of ACEIs or ARBs may have renoprotective effects greater than expected based on BP reduction alone. There has also been some criticism of some of the methodology and interpretation in this meta-analysis53-56. It was suggested that categorising BP changes into tertiles may have resulted in a loss of power and residual confounding. Additionally, omission of specific studies that support a renoprotective benefit for RAAS blockers, such as the Scandinavian diabetic nephropathy studies, might have affected the findings.

Choice of RAAS blocker for renoprotection

There is evidence that ACEIs and ARBs have renoprotective benefits independent of their BP-lowering effects. Which of the two classes confers optimal protection has yet to be determined, although the evidence currently appears to favour the ARBs in terms of improving both renal haemodynamics and clinical measures of renal function. Additional benefit is to be gained with the use of ARBs compared with ACEIs in terms of medication compliance and persistence57, an important factor to consider given the consequences of non-compliance. ACEIs are susceptible to the phenomenon of 'ACE escape', whereby long-term inhibition of ACE can stimulate non-ACE-dependent pathways, leading to the generation of angiotensin II with deleterious consequences58. ARBs can dramatically impede progression to overt nephropathy in patients with evidence of primary renal disease and can reverse early symptoms of renal impairment in patients with mild renal abnormalities. While ACEIs have shown positive effects against markers of renal disease, there is insufficient evidence to compare ACEIs against other classes of antihypertensive agents on endpoints such as time to ESRD. In contrast, ARBs have been shown to be superior to other classes in delaying renal disease progression37,39. The results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endoint Trial (ONTARGET59) are awaited to evaluate if ARBs or ACEIs offer the best renoprotection and to determine whether dual blockade with an ACEI and an ARB offers additional protective benefits over either monotherapy60. GFR dynamics and RAAS blockade: serum creatinine elevations

Substantial evidence supports the benefits of RAAS blockade for renoprotection. However, therapy with ACEIs or ARBs can result in a transient reversible increase in serum creatinine. This does not necessarily represent a matter of concern for the treating physician. As discussed, RAAS blockade decreases mean arterial pressure, thus reducing intraglomerular pressure in the nephrons, whilst simultaneously preventing the glomerulus from compensating through the normal angiotensin II-mediated vasoconstriction in the efferent arteriole. Accordingly, GFR declines temporarily and serum creatinine concentrations can rise. This is a purely functional, expected response, based on renal physiology and the dependence on the RAAS to maintain GFR, and should not be a reason to withhold or withdraw RAAS blockers. This transient elevation seen within the first 2 months of ACEI/ARB therapy is, in fact, strongly associated with long-term preservation of renal function61, and should be seen as a therapeutic success, reassuring the physician that the deleterious effects of angiotensin II have been circumvented. Withdrawal of the RAAS blocker should, however, be considered when a large increase in serum creatinine does not plateau within 4 weeks of initiating therapy, as this indicates the possibility of dehydration, drug-to-drug interactions, poor cardiac output or renal artery stenosis31,61.

Conclusions

Patients with renal dysfunction and hypertension require therapeutic strategies encompassing control of renal dynamics and appropriate BP lowering. RAAS inhibition provides renoprotection to patients with diabetic kidney disease and non-diabetic kidney disease with proteinuria. In these patients, RAAS blockers lower BP, reduce proteinuria, slow kidney disease progression, and reduce CV risk by mechanisms that are additional to lowering BP. Recent clinical trials have shown that ARBs are more effective than other antihypertensive drug classes in slowing the decline in GFR and onset of kidney failure in patients with albuminuria. The beneficial effect of ARBs in these studies was due to a combination of antihypertensive effects and haemodynamic, antiproteinuric and pleiotropic mechanisms. Current evidence suggests that ARBs may provide greater renoprotective benefits than ACEIs and have an important place in the treatment of high-risk patients.

Acknowledgements

Declaration of interest: Dr Ruilope has served as an advisor and speaker for MERCK, Sanofi-Aventis, Novartis, Bayer, Bristol Myers Squibb, GSK, Astra Zeneca and Menarine.

The author was assisted in the preparation of this text by professional medical writer Sharon Smalley (ACUMED, Tytherington, UK) and contracted medical writer Paul Hutchin; this support was funded by Novartis Pharma AG.

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CrossRef links are available in the online published version of this article:

http://www.cmrojournal.com

Paper CMRO-4412_5, 10:39-23.04.08

Accepted for publication: 27 February 2008

Published Online: 25 March 2008

doi: 10.1185/030079908X291921

Luis M. Ruilope

Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain

Address for correspondence: Luis M. Ruilope, Associate Professor of Internal Medicine, Complutense University, Head, Hypertension Unit, 12 de Octubre Hospital, Madrid, Spain. Tel.: +34 91 390 8284; Fax: +34 91 576 5644. ruilope@ad-hocbox.com

Copyright Librapharm May 2008

(c) 2008 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.

Source: Current Medical Research and Opinion

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