Published online before print November 14, 2005, doi: 10.1161/01.HYP.0000190586.07087.ca
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(Hypertension. 2005;46:1254.)
© 2005 American Heart Association, Inc.
Editorial Commentaries |
Reduction of Microalbuminuria by ß Blockers
Beyond Renin–Angiotensin System Blockade
From the Department of Nephrology, University of Heidelberg, Germany.
Correspondence to Eberhard Ritz, Department of Nephrology, University of Heidelberg, Heildelberg, Germany.
After the seminal observations of Mogensen, Parving, and Viberti, it has been increasingly recognized that, in diabetic patients, microalbuminuria predicts not only renal but also cardiovascular risk, and this is true for nondiabetic patients as well. This has led to the recommendation of more widespread testing of urine for microalbuminuria and the use of albuminnuria as a therapeutic target.1
The mechanism(s) underlying the link between microalbuminuria and cardiovascular risk have remained enigmatic. It is well known that there is crosstalk in the glomerulus between podocytes, the major barrier for the transit of albumin from the capillary to the filtrate, and endothelial cells. Such interaction is mediated mainly by vascular endothelial growth factor.2 It has remained enigmatic, however, how albuminuria, that is, podocyte dysfunction, is linked to dysfunction of endothelial cells outside of the glomerulus in the systemic circulation, as reflected by markers of endothelial cell dysfunction/microinflammation3 and by escape of albumin from the circulation into the extravascular space4 in microalbuminuric subjects.
In this issue, Bakris et al report the results of a prespecified secondary end point of the GEMINI trial conducted in hypertensive patients with type 2 diabetes.5 This part of the study was designed to examine the effects of different ß blockers, that is, metoprolol and carvedilol, on indices of albumin excretion. Following some early studies,6 it had been widely accepted that ß blockers have no substantial effect on albuminuria when compared with angiotensin-converting enzyme (ACE) inhibition. The results of the present study go beyond past data and are remarkable as well as solid: in contrast to previous studies, target blood pressure was reached in most patients, and all of the patients were on RAS blockade with ACE inhibitors or angiotensin receptor blockers.
The salient results are, first, that the addition of ß blockers reduced urinary albumin concentration in microalbuminuric subjects, caused less progression from normoalbuminuria to microalbuminuria, and, at least for carvedilol, caused additional reduction of urinary albumin concentration, even in normoalbuminuric patients. These results were not explained by differences in blood pressure. Whether a similar beneficial effect would still have been seen in patients on higher doses of ACE inhibitors or angiotensin receptor blockers is unknown. Second, at the doses used, carvedilol was superior to metoprolol in reducing albuminuria. This information is interesting to the clinician for several reasons.
Although RAS blockade is highly successful in reducing albuminuria, it is not uniformly effective or persistent in all of the patients, even when blood pressure targets have been reached, particularly in more advanced stages of diabetic nephropathy. For this reason, any additional possibility of intervention in diabetic patients is most welcome indeed. Because albuminuria is an important predictor of renal7 and cardiovascular8 risk in nondiabetic individuals as well and because reduction of albuminuria reduces the risk of cardiovascular events,9 the importance of the finding of Bakris may have implications beyond diabetes.
Why carvedilol was superior to metoprolol is not perfectly clear. Bakris discussed the potential roles of better glycemic control and of reduction of oxidative stress by carvedilol.
Why was ß blockade additive to the effect of RAS blockade? One point to consider would be a more intense reduction of the activity of the RAS in the juxtaglomerular apparatus, as well as possibly in local intrarenal RAS systems, for example, in podocytes,10 mesangial cells,11 and proximal tubular cells.12 The importance of local RAS is illustrated by the findings of Nishiyama et al,13 where the maximal blood pressure-lowering doses of enalaprilate reduced angiotensin II concentrations in the circulation but not in the renal interstitium. On the other hand, one cannot definitely exclude a direct effect of ß blockers on podocytes, the gatekeepers of glomerular albumin transit, because catecholamines are known to modulate podocyte function.14
For another reason, the findings of Bakris are also of more general interest. The importance of sympathetic overactivity in renal disease had, in the past, been grossly underestimated. Today, we know from studies using microneurography that the sympathetic activity may be increased in subjects with renal disease even when glomerular filtration rate (GFR) is still normal,15 and it is almost uniformly increased in more advanced stages of renal failure. Reduction of sympathetic activity by the centrally sympathicoplegic agent moxonidine caused blood pressure-independent reduction of albumin excretion in microalbuminuric diabetic individuals.16 The blood pressure-independent reduction of albuminuria by peripheral sympathetic blockade does, therefore, make absolute sense.
There is one final point. Particularly when diabetic patients have reached more advanced stages of renal disease, it is virtually impossible to achieve target blood pressure using only 1 or 2 antihypertensive agents. The clinician is, therefore, looking out for rational arguments when selecting agents for antihypertensive drug combinations. For this choice, the findings of Bakris provide another valid argument.
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Footnotes |
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The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association.
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References |
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