Department of Internal MedicineNephrology, Charité, Humboldt University, Berlin and 1 Department of Internal Medicine, Ruperto Carola University Heidelberg, Heidelberg, Germany
Correspondence and offprint requests to: Harm Peters, MD, Department of Internal MedicineNephrology Charité, Campus Charité-Mitte, Humboldt University, Schumannstraße 2021, D-10117 Berlin, Germany. Email: harm.peters{at}charite.de
Keywords: angiotensin II; TGF-ß; fibrosis
Antihypertensive treatment and progression of renal disease
It has been well established that at least in proteinuric renal disease, progressive loss of renal function can be effectively diminished, or even prevented, by antihypertensive treatment. This principle has been exemplified by early studies of Danish diabetologists [1,2] who administered beta-blockers, hydralazine and diuretics to patients with type 1 diabetes and nephropathy. The beneficial effect of lowering blood pressure has also been well established in non-diabetic renal disease [3].
More recently, it has also been shown that treatment with angiotensin-converting enzyme (ACE) inhibitors provides benefit with respect to progression which goes beyond lowering of blood pressure. This has been documented both for diabetic [4] and non-diabetic glomerular disease [5,6]. This therapeutic superiority has been ascribed to an antiproteinuric effect of pharmacological blockade of the reninangiotensin system (RAS) by ACE inhibitors and possibly also by angiotensin receptor blockers [7] which is partially blood pressure-independent. This notion is supported by the demonstration that the benefit derived from ACE inhibitor treatment is greater in patients with more severe proteinuria [6]. It is of interest that ACE inhibitors progressively lose their antiproteinuric superiority compared with other antihypertensive agents when blood pressure is reduced progressively to ever lower values within the range of normotension; this is true both for the antiproteinuric action [8] and for renal events (E. Lewis, personal communication).
Target blood pressure
Based on the results of the Modification of Diet in Renal Disease (MDRD) Trial [9] and other studies, it recently has been proposed that target blood pressure values substantially lower than normotension according to WHO or JNC VI criteria are optimal for patients with diabetic or non-diabetic proteinuric renal disease [10].
Unsatisfactory response to ACE inhibitors
Even though today we have the powerful instruments to lower blood pressure substantially and achieve specific pharmacological blockade of RAS, we are still confronted with patients whose proteinuria and loss of renal function is not controlled satisfactorily by this approach. Based on experimental results and preliminary clinical observations, we advance the hypothesis that in this circumstance the dose of ACE inhibitors should be increased further until a more satisfactory decrease in the rate of protein excretion and progression is achieved.
Experimental models of progression: importance of extracellular matrix accumulation
Glomerular and interstitial fibrosis parallels the progressive loss in renal function in experimental and human renal disease. There is substantial evidence that angiotensin II, independently of its vasoconstrictor action, directly activates mesangial cells, possibly podocytes, renal tubular epithelial cells and interstitial fibroblasts [11]. These effects are mediated mainly by the angiotensin II receptor subtype AT-1, but some effects of angiotensin II, e.g. chemotaxis, are apparently mediated via AT-2 receptors [12].
Chronic infusion of subhypertensive doses of angiotensin II was shown to cause interstitial fibrosis of the kidney [13]. Serum proteins, particularly oxidized lipoproteins, iron-binding proteins and complement factors, are considered to be nephrotoxic [14] and conversely ACE inhibitors by virtue of their antiproteinuric action apparently have blood pressure-independent renoprotective action, but the above cell activation of angiotensin II provides a further rationale for the use of drugs blocking the RAS.
Dose of ACE inhibitor angiotensin receptor blocker and renal damage in experimental models
Recent experimental findings have been pertinent to the issue of whether increasing the dose of ACE inhibitors provides further renoprotection in a blood pressure-independent fashion. Based on the idea that accumulation of extracellular matrix, mediated via the action of transforming growth factor-ß (TGF-ß), plays a key role in development of fibrosis, a recent study using the Thy-1 model of mesangioproliferative glomerulonephritis investigated the effects of increasing doses of the ACE inhibitor enalapril or the angiotensin II receptor blocker losartan on TGF-ß expression and matrix accumulation [15]. The underlying idea was that reduction in TGF-ß overexpression should maximize the above-described antifibrotic action of angiotensin II blockade in renal disease. This is plausible in view of the fact that TGF-ß promotes fibrogenesis in this model of acute wound repair. In this study, both enalapril and losartan reduced glomerular TGF-ß overexpression and matrix expansion in a dose-dependent manner [15]. The reduction was moderate with relatively low doses which were sufficient to control blood pressure. Maximal reduction in TGF-ß expression, however, clearly required higher doses, in agreement with past reports [16]. Glomerular fibronectin and plasminogen-activation-inhibitor-type, both sensitive markers of TGF-ß action, paralleled expression of TGF-ß. However, even at maximally effective doses, enalapril or losartan failed to normalize TGF-ß production and matrix expansion. We conclude from these findings that maximal antifibrotic benefit from angiotensin II blockade requires higher doses than needed to normalize blood pressure.
Preliminary clinical evidence
These experimental findings are in good agreement with some clinical observations [17, Fliser and Ritz, unpublished]. In 16 patients with IgA glomerulonephritis and normal glomerular filtration rate at a sodium intake of 80 mmol/day, Paller et al. administered lisinopril at increasing doses of 5, 10, 15 and 20 mg/day for 4 weeks per period with 3 weeks of washout. Blood pressure decreased by 22% with the lowest dose and no further decrease was seen at higher doses, but proteinuria progressively decreased by 39, 44, 61 and 67% with progressively higher doses. There was a significant correlation between dose of lisinopril and reduction of proteinuria (r=0.88). This observation parallels to some extent the finding in the Atlas study in congestive heart failure, where increasing the dose of lisinopril further reduced the rate of fatal and non-fatal events (M. Pacher et al., Annual Meeting of the American College of Cardiology, 1998, Atlanta). It is possible that so far full benefit from ACE inhibition has not been uniformly obtained in renal patients because of (i) underdosing and (ii) frequent failure to sensitize the organism to the effect of ACE inhibition by inducing a negative sodium balance.
ACE inhibition, receptor antagonism or a combination of both?
With the availability of angiotensin receptor blockers, it becomes an issue of practical importance (i) whether one drug is superior to the other and (ii) whether combination of both is superior to single treatment [15]. At the moment, head-on-comparison [7] shows that ACE inhibitors and AT-1 receptor blockers are equieffective in reducing albuminuria. Only two ongoing studies on angiotensin II receptor blockers in type 2 diabetes with renal failure will give more definite answers, however, about their efficacy to halt progression. We have to wait for the results until the next millennium.
In the experiment using Thy-1 glomerulonephritis mentioned above [15], it was shown that maximally effective doses of enalapril or losartan down-regulated pathological TGF-ß expression and matrix expansion to a similar extent. The combination of both drugs did not result in additive benefit. To the extent that one can extrapolate from experimental models to glomerular disease in man, it would be unwise to put too much hope into the combination of ACE inhibitors and angiotensin receptor blockers, at least as far as the renal effects are concerned, despite some encouraging recent preliminary observations [18].
Conclusion
Although we are painfully aware that controlled information in humans is not available, based on experimental data and preliminary clinical observations, we propose that the dose of ACE inhibitors should be increased even if target blood pressure values [10] have been reached in order to minimize further the rate of urinary protein excretion and to slow the progressive course of chronic renal disease more effectively.
References