Renal protection with angiotensin receptor blockers

JNEPHROL 2011; 24 ( 05 ) : 569-580

REVIEW

DOI:10.5301/JN.2011.6445

Renal protection with angiotensin receptor blockers: where do we stand?

Roland E. Schmieder 1, Luis-Miguel Ruilope 2, Anthony H. Barnett 3

Abstract The increasing burden on health care providers from chronic kidney disease (CKD) is due to the escalating prevalence of obesity, hypertension and type 2 diabetes. The gradual decline in kidney function in the presence of these risk factors is also associated with increased cardiovascular disease. Excess angiotensin II production by the renin-angiotensin system is responsible, at least in part, for development of hypertension and for damage in the kidneys and the cardiovascular system. Pharmacological targeting of the renin-angiotensin system not only reduces blood pressure, but may also provides more direct vascular protection. Angiotensin receptor blockers (ARBs) are better tolerated than angiotensin-converting enzyme inhibitors and, thus, may be a more practical therapeutic option. Clinical studies have demonstrated the efficacy of irbesartan, losartan, telmisartan and valsartan in the management of CKD. All ARBs tested to date have proved effective in improving at least some aspects of renal dysfunction. Few within-class comparative studies exist. Telmisartan provides superior reductions in proteinuria to losartan, however, even when blood pressures are equalized with concomitant antihypertensives. This superiority is probably linked to higher receptor affinity, longer plasma half-life and higher lipophilicity of telmisartan compared with other ARBs. The reduction of proteinuria with ARBs is also linked to improved cardiovascular outcomes. After a

Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen - Germany 2 Nephrology Service, Hypertension Unit, Hospital of 12 October, Madrid - Spain 3 Division of Clinical and Experimental Medicine, University of Birmingham and Diabetes Centre, Heart of England NHS Foundation Trust, Birmingham - UK 1

decade of research, there is now substantial evidence to show that the use of ARBs provides an efficacious treatment option for the prevention of renal disease progression in patients with hypertension and/or diabetes.

Key words: Angiotensin receptor blockers, Chronic kidney disease, Irbesartan, Losartan, Renal protection, Telmisartan, Valsartan

Introduction Chronic kidney disease (CKD) has reached epidemic proportions. The most comprehensive information on its prevalence in developed countries comes from the National Health and Nutrition Examination Surveys (1). Based on the presence of albuminuria and decreased estimated glomerular filtration rate (eGFR), the prevalence of CKD stages 1-4, as defined by the National Kidney Foundation (2), increased from 10.0% in the period 1988-1994, to 13.1% between 1999 and 2004 (1). Similar prevalences have been reported in the United Kingdom (3), Germany (4) and Spain (5). If CKD is not diagnosed and aggressively treated in its early stages, many patients will progress to end-stage renal disease (ESRD) and will require either a kidney transplant or dialysis to avoid premature death. Many other patients with CKD will die of cardiovascular (CV) disease. According to the US

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Schmieder et al: Renal protection with ARBs

Renal Data System, the incidence of ESRD in the United States in 2006 was 360 per million (6). The availability of kidneys for transplantation is limited, and dialysis is costly, placing heavy demands on health care resources. The dramatic increase in CKD in recent years has been attributed to the escalating prevalence of obesity (7), diabetes (7, 8) and hypertension (9), and diabetic nephropathy is the overriding reason for ESRD in Europe (10) and the United States (11). The problem of CKD presents an even greater challenge to developing countries (12).

The renal disease continuum The concept of a continuum of pathophysiological changes mediated by angiotensin II was first conceived for the progressively increasing severity of CV disease in the presence of risk factors (13). A similar gradual transition takes place within the renal vasculature, resulting in kidney disease of increasing severity. The initial, subclinical damage to glomerular endothelium induced by such risk factors as hypertension and/or diabetes, and the consequent endothelial dysfunction, may be due (at least in part) to excess angiotensin II production that results in oxidative stress (14, 15). Subsequent glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis lead to incipient disease, identified by microalbuminuria (16). Further damage occurs in the absence of pharmacological intervention, with the emergence of overt nephropathy, defined as the presence of macroalbuminuria or proteinuria. Thereafter, there is a gradual decline in the GFR and an increase in serum creatinine levels that culminates in ESRD.

Interrelationship between CV disease and CKD Because of the similarity between the pathophysiological effects of angiotensin II on the CV system and the renal vasculature, it seems logical to suppose that CV disease and CKD progress simultaneously. Most individuals with CKD die of coronary heart disease (CHD) before end-organ damage occurs in the kidneys (17). Similarly, patients with CV disease often exhibit varying degrees of CKD. The presence of microalbuminuria has long been identified as a marker of CKD; now, it is acknowledged as a predictor of CV morbidity and mortality (18-20). Even low-grade microalbuminuria (i.e., >30 mg/24 hours) is associated with increased CV risk in apparent healthy patients (21). Recent data from a longterm follow-up of hypertensive patients showed that development of CKD was strongly and independently associated with a poor CV prognosis (22). Furthermore, the presence 570

of proteinuria increased the risk of a future CV event to the same extent as a prior myocardial infarction (MI) (23). eGFR also serves as a marker of CV risk. A recent population study performed in Reykjavik identified a 33% increase of CHD in apparently healthy adults if their eGFR was 160 mm Hg. A reduction of the dose of either study drug was also allowed after 2 months. There was no significant difference in the change in GFR from baseline with telmisartan (–17.9 ml/min per 1.73 m2) versus enalapril (–14.9 ml/min per 1.73 m2). The treatment difference was –3.0 9 ml/min per 1.73 m2 (95% CI, –7.6 to 1.69); since the lower boundary of the 95% CI was greater than the predefined margin of –10.0 ml/min per 1.73 m2, the primary objective of the study – the noninferiority of telmisartan compared with enalapril – was demonstrated. DETAIL also examined the annual changes from baseline in the GFR. The greatest fall in GFR was observed after the first year in both treatment arms; this may be explained by the hemodynamic effects, with a consequent reduction in intraglomerular pressure (50). Thereafter, the rate of decline in GFR slowed, with no significant differences with the 2 treatments. The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study was carried out to determine the long-term renal protection provided by different doses of telmisartan in 527 Japanese patients with incipient nephropathy (urinary albumin to creatinine ratio [UACR] 100-300 mg/g and serum creatinine concentration