Department of Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, UK.
Correspondence and requests for reprints to H. Thurston, Department of Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK. Tel: +44 0116 252 3183; fax: +44 0116 252 3273; e-mail: firstname.lastname@example.org
The paper by Berger et al.  in this issue of the journal, which reports an additive anti-proteinuric effect with combination angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonist treatment, may herald a further step in the quest to ameliorate the progressive decline in renal function suffered by patients with diabetic and non-diabetic renal disease. In this study, the addition of a fixed dose of the AT1 receptor antagonist (candesartan) to the pre-existing non-standardized ACE inhibitor antihypertensive regime of patients with chronic glomerulonephritis resulted in a significant reduction in proteinuria. Although this was associated with a small but significant fall in blood pressure, there was no significant change in glomerular filtration or renal blood flow.
It is well established that hypertension not only complicates, but also accelerates the decline of renal function in patients with chronic proteinuric glomerular disease  and good blood pressure control not only reduces urinary protein but also delays the progression to end-stage renal failure [3,4]. Moreover, in large trials, ACE inhibitor-based treatment appears to provide superior protection than conventional antihypertensive agents, even when similar levels of blood pressure control are achieved [5–7]. Unfortunately, in many patients with renal disease, ACE inhibitors alone fail to lower blood pressure to target levels. Also, it is well known that plasma angiotensin levels may remain normal or become elevated during long-term treatment [8,9]. This may reflect the competitive nature of ACE inhibitor action or the continued generation of angiotensin II by non-ACE pathways, including human chymase [10,11].
AT1 receptor antagonists have a significant advantage over ACE inhibitors because these agents specifically inhibit angiotensin II binding to the receptor which is responsible for most of the cardiovascular actions of angiotensin II. Furthermore, AT1 receptor antagonists do not interfere with kinin breakdown and cough is not associated with their use. Several trials have reported a reduction in proteinuria in type II diabetes mellitus during treatment with the AT1 receptor antagonist irbesartan [12,13] and the recently published RENAAL study  demonstrated a significant reduction both in the incidence of serum creatinine doubling and progression to end-stage renal failure. Also, there was a decrease in hospital admissions for heart failure; however, there was no change in overall death rate. On the other hand, Gansevoort et al.  showed that the AT1 receptor antagonist losartan had similar effects to the ACE inhibitor enalapril on renal function in diabetes. Consequently, combination ACE inhibitor/AT1 receptor antagonist therapy is a tempting proposition because it is likely that blockade of the renin–angiotensin system would be more complete. Moreover, any benefit of ACE inhibitor-induced kinin potentiation would be retained.
Although limited, the evidence for a favourable interaction between ACE inhibitors and AT1 receptor antagonists has clearly emerged from recent studies. An enhanced hypotensive effect has been demonstrated in salt-depleted normotensives  and in patients with essential hypertension . Similarly, the CALM study  showed that whilst the ACE inhibitor lisinopril was as effective in reducing blood pressure as the AT1 receptor antagonist candesartan, combination candesartan/lisinopril treatment produced an additional hypotensive effect. In addition, this combination produced a significantly greater reduction of the urinary albumin/creatinine ratio than either drug alone. There is also a small body of evidence suggesting that combination ACE inhibitor/AT1 receptor antagonist therapy may be beneficial in patients with chronic glomerular disease. Thus, the addition of the fixed dose of the AT1 receptor antagonist losartan to non-standardized ACE inhibitor therapy significantly reduced proteinuria in eight patients with immunoglobulin A (IgA) nephropathy . Similar benefits were observed in long-term trials where blood pressure control with a combination of the ACE inhibitor enalapril and the AT1 receptor antagonist losartan was compared with that obtained using conventional (atenolol, hydralazine or methyldopa) antihypertensive treatment  in 41 patients with biopsy-proven IgA nephropathy. Treatment with the ACE inhibitor/AT1 receptor antagonist combination resulted in significant reduction in proteinuria in 10 of the 21 patients and, overall, a slight improvement in serum creatinine. By contrast, a significant rise in serum creatinine with no change in proteinuria was observed in the control group.
Two groups have investigated the effect of combination ACE inhibitor/AT1 receptor antagonist treatment in proteinuric chronic glomerulonephritis. Ferrari et al.  used a double-blind crossover design comparing the response to a fixed dose of the ACE inhibitor, fosinipril, or the AT1 receptor antagonist, irbesartan, alone or in combination. Ten patients underwent three 6-week periods of treatment separated by 4-week washout periods and 24-h ambulatory blood pressure was recorded before and at the end of each treatment period. Combined ACE inhibitor/AT1 receptor antagonist blockade led to a 58% reduction in proteinuria compared with the 32% fall achieved by monotherapy. Moreover, the increased antiproteinuric effect was not associated with a significant change in creatinine clearance. Fosinopril and irbesartan monotherapy produced a similar blood pressure-lowering and although there was a small additional hypotensive response with combination treatment, there were no significant differences between the three treatment periods. Moreover, there was no correlation between the change in 24-h ambulatory blood pressure and the change in proteinuria. Berger et al.  employed a placebo-controlled, double-blind randomized study in which a fixed dose of the AT1 receptor antagonist candesartan or a placebo was added to the existing non-standardized ACE inhibitor treatment of 12 patients for 8 weeks. Again, 24-h ambulatory blood pressure was recorded but, in addition, glomerular filtration rate and renal plasma flow measurements were performed using inulin and p-aminohippurate clearance. The addition of candesartan caused a significant decrease in urine protein from 2.0 ± 0.4 g/day to 1.3 ± 0.3 g/day without significant change in glomerular filtration rate or renal plasma flow. However, the candesartan/ACE inhibitor combination also produced a significant reduction in both systolic and diastolic blood pressure and this may have contributed to the enhanced anti-proteinuric effect.
Clearly, these studies have a number of limitations. In particular, the use of non-standardized ACE inhibitor treatment which was not titrated to the maximum dose, small group sizes and short treatment periods (6–8 weeks). The mechanism by which combination ACE inhibitor and ARA treatment provides an enhanced anti-proteinuric effect remains to be determined. There seems to be little evidence for a significant change in glomerular filtration rate; however, several studies, including that of Berger et al. , have demonstrated an additional fall in blood pressure with combination treatment. Nonetheless, the change in blood pressure was small and it is tempting to attribute the greater anti-proteinuric effect to more complete angiotensin inhibition. An alteration in glomerular basement membrane pore selectivity [22,23] or decreased mesangial matrix production  and mesangial cell proliferation  could mediate the reduction in proteinuria. Whatever the mechanism, all of the dual angiotensin blockade studies consistently show an enhanced anti-proteinuric effect. Unfortunately, this is a surrogate end-point. The question of whether combination ACE inhibitor/AT1 receptor antagonist treatment slows the decline in renal function and postpones end-stage renal failure in these patients remains to be addressed in future studies.
Only a large, long-term, prospective, parallel group, multicentre trial can determine whether this treatment approach will have a significant impact on progressive renal function loss in patients with chronic glomerulonephritis.
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