Zenon's paradox or how much to lower blood pressure for optimal renoprotection

Gunter Wolf

Klinik für Innere Medizin III, Friedrich-Schiller-University, Jena, Germany

Correspondence and offprint requests to: Prof. Gunter Wolf, Klinik für Innere Medizin III, University Hospital Jena, Erlanger Allee 101, D-07747 Jena, Germany. Email: gunter.wolf{at}med.uni-jena.de

Keywords: progression of renal disease; blood pressure; proteinuria; angiotensin II; ace inhibitor



   Introduction
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 
The Greek philosopher Zenon, who lived almost 2500 years ago, came up with strange ideas. One is the famous race between Achilles, the fastest runner of Greek mythology, and an old tortoise [1]. Achilles, as a true hero, agreed to give the tortoise an advantage and the tortoise started 10 m in front of Achilles. For Achilles to get in front of the tortoise, he first had to run to the place where the tortoise started. But in that time the tortoise had covered some distance, which Achilles now had to run in order to catch up. However, in this time again the tortoise had gone some distance and Achilles was still behind the tortoise. This process continued forever and apparently Achilles could never pass the tortoise. Our everyday experience suggests that Achilles, even suffering acute problems with his heels, could easily pass the tortoise. Nevertheless, Zenon's arguments are appealing and therefore this problem is called a paradox. This classic story reminds me of some paradoxes of current nephrology: how much should we reduce blood pressure for optimal renoprotection in chronic renal diseases? Does the type of antihypertensive drug matter? Is albuminuria rather than blood pressure a target for treatment with antihypertensive agents? And, could we ever win the race and not only halt progression but also stimulate regression of chronic renal diseases?



   The REIN-2 study
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 
Ruggenenti et al. [2] recently perplexed the renal community somewhat with a multicentre, randomized controlled trial showing that in patients with non-diabetic proteinuric nephropathies who received background ACE inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown (the so-called REIN-2 study). In this trial, patients with non-diabetic proteinuric nephropathies were assigned, after a 6 week washout period, to either conventional (diastolic <90 mm Hg, irrespective of systolic blood pressure, n = 169) or intensified (systolic/diastolic <130/80 mm Hg, n = 169) blood pressure control [2]. Both groups received background treatment with the ACE inhibitor ramipril (2.5–5 mg/day) and patients in the intensified blood pressure group received additional therapy with the dihydropyridine calcium-channel blocker felodipine (5–10 mg/day). Moreover, both groups were treated with additional antihypertensive drugs such as ß-blockers, {alpha}/ß-blockers, antiadrenergic substances and diuretics. The primary outcome measure was time to end-stage renal disease over a 36 month follow-up. Although felodipine on top of ramipril significantly lowered systolic and diastolic blood pressure by 4 and 3 mm Hg, respectively, throughout the follow-up compared with the conventional group (no calcium channel blocker, only ramipril), the intensified regimen had no additional benefits for residual proteinuria, decline of glomerular filtration rate and progression to end-stage renal disease [2]. Despite some weaknesses (no histological diagnoses are given, and some inconsistencies in other antihypertensive drugs, particularly antiadrenergic drugs in the two study groups), the trial appeared well designed and the drop-out rate was low. Are the findings of Ruggenenti and colleagues really surprising and do they question the holy grail that hypertension is a major determinant of renal disease progression?



   Blood pressure control and nephroprotection
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 
In a landmark study, Parving et al. [3] were among the first to provide evidence that lowering blood pressure could slow the rapid downhill course of renal function in type 1 diabetic patients with nephropathy. This effect was achieved with ß-blockers and diuretics [3]. The Modification of Diet in Renal Diseases Study (MDRD) consisted of two randomized clinical trials [4] performed in a total of 840 patients who had chronic renal diseases of diverse causes, mainly glomerulonephritis and polycystic kidney diseases (only 3% diabetic patients). Although this study failed to convincingly prove the benefit of a low protein diet in slowing the progression of renal diseases [4], the trial showed that patients with a targeted blood pressure of <125/75 mm Hg had better renal function in the follow-up than those with the target of 140/90 mm Hg [5]. The long-term follow-up (7 years) of the MDRD study confirmed that a low targeted blood pressure delayed the onset of renal failure and a composite outcome of kidney failure and all-cause mortality [6]. However, the rate of GFR decline in the initial study was unrelated to blood pressure in patients with baseline proteinuria <0.25 g/day [5]. In contrast, the interaction of baseline proteinuria with blood pressure was not statistically significant in the long-term follow-up MDRD study, probably because of limited power [6]. Interestingly, in the original MDRD study 48% patients in the lower blood pressure group were treated with ACE inhibitors versus 28% in the target of 140/90 mm Hg group. In the long-term follow-up analysis even more patients in the lower blood pressure group received ACE inhibitors (51 vs 32%). Although it is tempting to speculate that the better outcome in the low blood pressure group was caused by use of ACE inhibitors rather than by blood pressure lowering itself, additional adjustments for the use of ACE inhibitors in the long-term follow-up trial did not substantially change the results [6].

The blood pressure-dependent findings of the MDRD study were not supported by the The African American Study of Kidney Disease and Hypertension trial, which showed no additional benefit of lower blood pressure (mean arterial pressure 92 mm Hg or lower) in slowing the progression of hypertensive nephropathy in African American patients [7]. Moreover, the trial provided evidence that ACE inhibitors appeared to be more effective than ß-blockers or dihydropyridine calcium channel blockers in slowing GFR decline [8].

The Hypertension Optimal Treatment study assigned patients with hypertension of three different groups with diastolic blood pressure targets (≤80, ≤85, ≤90 mm Hg) [8]. No significant changes in serum creatinine or calculated creatinine clearance were seen at the end of the 3.8-year treatment without influence of the blood pressure reached [8]. However, there were some problematic issues with this study, including the lack of serum creatinine measurements in 3.3% of patients who died during the study, a rather low rate of cardiovascular events in this study, and the recent insight that systolic blood pressure is more important for renal injury than diastolic blood pressure. Neither was there a difference between intensive (132/78 mm Hg) and moderate (138/86 mmHg) blood pressure control in stabilizing renal function in hypertensive type 2 diabetics without albuminuria in the Appropriate Blood pressure Control in Diabetes trial [9]. Thus, there are some studies that could not find additional renal protection by further blood pressure lowering in patients with chronic nephropathies.



   ACE inhibitors and nephroprotection
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 
Compelling evidence based on prospective randomized and controlled clinical trials has shown that ACE inhibitors are renoprotective, independent of antihypertensive effects, in diabetic and non-diabetic renal diseases (for review see [10]). A meta-analysis of 11 randomized, controlled trials comparing the efficiency of antihypertensive regimens with or without ACE inhibitors for patients with predominantly non-diabetic renal disease was performed by Jafar et al. [11]. In this analysis, systolic blood pressures of 110–129 mm Hg and proteinuria <2.0 g/day were associated with the lowest risk for progression. ACE inhibitors remained beneficial after adjustments for blood pressure and urine protein excretion suggesting that pleiotropic effects of ACE inhibitors beyond blood pressure and proteinuria reduction may play a role [11]. A systolic blood pressure <110 mm Hg was associated with a higher risk for kidney disease progression, independent of the degree of proteinuria [11]. This finding may be explained by the fact that a systolic blood pressure of <110 mm Hg could facilitate renal hypoxia, a finding observed in some animal models.

How can the superiority of ACE inhibitors be explained? There is a deluge of data indicating that angiotensin II (ANG II) is the most important single factor responsible for progression of renal disease [12]. These findings originated with the landmark study by Anderson et al. [13], who demonstrated that an ACE inhibitor limited glomerular injury in rats with experimentally induced reduction in renal mass. Although at that time it was clear that the protective effects of ACE inhibitor treatment were apparently independent of blood pressure, it was then thought that a reduction of the increased glomerular capillary pressure is the main effect of ACE inhibitor treatment [13]. Subsequently, it became clear that ANG II exhibits many other non-haemodynamic effects [12]. First, ANG II is a major mediator of proteinuria through haemodynamic (hyperfiltration) and structural effects (suppression of nephrin, inhibition of proteoglycan synthesis, remodelling of the glomerular basement membrane through stimulation of extracellular matrix synthesis and inhibition of matrix degradation). This increase in proteinuria is probably the important trigger, stimulating the development of glomerulosclerosis, interstitial fibrosis and tubular atrophy, as initially proposed by Bertani et al. [14]. Fatally, proteinuria itself contributes to further activation of the renin angiotensin system in intrinsic renal cells, making this an amplifying circle. Secondly, ANG II exhibits proinflammatory and profibrogenic effects by locally inducing chemokines, cytokines and growth factors in renal cells [15]. Thirdly, ANG II further amplifies deleterious effects of proteinuria, for example by facilitating uptake of ultrafiltered proteins in proximal tubular cells and synergistic signal transduction pathways leading to the secretion of chemokines. Therefore, inhibition of the renin angiotensin system is of utmost importance for protecting the kidney in chronic renal injury.

Since there are other pathways involved in the formation of ANG II besides ACE (e.g. chymase) that are active under pathological conditions, ACE inhibitors, particularly in currently used dosages, are not sufficient to totally block intrarenal ANG II formation [16]. On the other hand, ANG II or its degradation products may exert pathophysiological effects through binding to receptors other than AT1, indicating that some deleterious effects of ANG II would not be antagonized by sartans [16]. Finally, some ACE inhibitors and certain sartans also have, at least in experimental settings, direct effects on cells without involvement of ANG II [16]. Consequently, combination therapy with ACE inhibitors and AT1-receptor blockers could offer additional benefits. Indeed, a recent study demonstrated superior effects of the combination therapy in reducing proteinuria and slowing the progression of non-diabetic renal disease [17]. Notably, this effect was not caused by better blood pressure control of the combination therapy.



   Proteinuria as a primary target?
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 
The REIN-2 study should stimulate our efforts to use and titrate drugs not only for their blood pressure lowering effects, but also for their potency to reduce albuminuria. A recent preliminary study, which is in some aspects the other side of the coin of the REIN-2 study, showed that absence of blood pressure response to the AT1-receptor blocker losartan did not preclude a reduction in albuminuria [18]. Moreover, in patients who had already reached the desired blood pressure, a further increment in the AT1 receptor did result in a progressive fall in proteinuria [18]. However, Ruggenenti et al. [2] did not primarily study whether further lowering of blood pressure might be beneficial for cardiovascular outcomes, although fatal and non-fatal serious cardiovascular events were comparable in both groups during the study period. Whether a further reduction of blood pressure on the background of ACE inhibitor treatment by other drugs than calcium antagonists would also fail to confer additional renal protection is currently unknown. In this regard, many experimental and clinical studies have shown that dihydropyridine calcium antagonists could have adverse effects on renal function in chronic nephropathies [19]. Taken together, an interesting trial such as the REIN-2 study is thought to be provocative, controversial, raises new questions, and asks for further investigations.

What Zenon did not know is that it is possible to add numbers and numbers without reaching infinity. If the numbers are decreasing (e.g. 1 + 0.1 + 0.01 + 0.001 ···) the sum will converge and Achilles could easily pass the tortoise. The mathematical solution to Zenon's paradox had to wait for the independent discovery of calculus by Leibniz and Newton. Likewise, we have to wait for better insights into the mechanisms by which interference with the renin angiotensin system prevents progression of renal diseases. Fascinating recent experimental studies show that very high doses of ACE inhibitors or AT1-receptor blockers might induce regression of established renal fibrosis [20–22]. Zenon, who believed that the world of senses is an illusion, would not be surprised at all.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 The REIN-2 study
 Blood pressure control and...
 ACE inhibitors and...
 Proteinuria as a primary...
 References
 

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