Antihypertensive therapy and progression of chronic kidney disease: Experimental studies

INTRODUCTION — Extensive studies in animals and humans have shown that progression of a variety of chronic kidney diseases may be largely due to secondary hemodynamic and metabolic factors, rather than the activity of the underlying disorder. Identification of these factors, such as intraglomerular hypertension and glomerular hypertrophy, is important clinically because they can be treated, possibly preventing or minimizing further glomerular injury [1-3]. A review of the mechanisms by which these alterations might occur and how they might induce glomerular injury is available elsewhere. (See "Secondary factors and progression of chronic kidney disease".)

An important component of this approach is antihypertensive therapy with blockers of the renin angiotensin system (RAS), specifically use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The experimental studies supporting this approach will be reviewed here. The clinical trials and recommendations are presented separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

PREFERENTIAL EFFECT OF RAS BLOCKERS ON RENAL HEMODYNAMICS — From a therapeutic viewpoint, lowering systemic blood pressure is beneficial in a variety of experimental kidney diseases, at least in part by reducing intraglomerular pressure [1,2,4-6]. Renin angiotensin system (RAS) blockers, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), appear to be particularly effective in this regard; this effect may be related to reversal of the angiotensin II-induced increase in resistance at the efferent or postglomerular arteriole [4,5]. Dilation of the efferent arteriole will facilitate blood movement out of the glomerulus, lowering the intraglomerular pressure independent of any change in systemic blood pressure. A brief review of the actions of angiotensin II on glomerular hemodynamics is available elsewhere. (See "Renal effects of ACE inhibitors in hypertension".)

It is presumed that the deleterious effect of angiotensin II represents local generation since circulating levels are normal or reduced (due to volume expansion) in many patients with chronic kidney disease [7]. In the remnant kidney model of chronic kidney failure, for example, endothelial injury or activation is associated with enhanced expression of angiotensinogen mRNA, which may then lead to increases in angiotensinogen and angiotensin II production [8].

Angiotensin receptor blockers — Data in animal models have found that ARBs are as effective as ACE inhibitors [9-13], albeit with a lesser antiproteinuric effect [14,15].

With experimental models, some variability in results may be due to differences in dosing, which was mostly based on the maximal blood pressure reductions. In some experimental studies, much higher levels of the angiotensin-I receptor are noted in kidney parenchyma than in vascular smooth muscle cells [16]. This suggests that higher doses of ARBs may be required to effectively block kidney parenchymal receptors than the doses used to lower blood pressure. These much higher doses may confer effects beyond that obtained with blood pressure lowering, particularly decreased inflammation and superior nephroprotection.

This hypothesis was evaluated in the 5/6 renal ablation model in which conventional doses of losartan (L50), supplemented with hydrochlorothiazide and hydralazine to achieve similar blood pressures, were compared with 10-fold higher doses of losartan (L500) [17]. Among the effects measured, glomerular pressure and glomerular filtration rate were similar with both L50 and L500, although blood pressure and renal vascular resistance were lower with L500. Although kidney injury and albuminuria were partially reduced by L50 at four months postsurgery, L500 completely arrested kidney inflammation and injury and was associated with regression of albuminuria. This finding suggests that full blockade of angiotensin-I receptors requiring much higher doses of ARBs may be associated with maximum nephroprotection.

Human studies show that ACE inhibitors and ARBs have similar benefits on albuminuria and progression of kidney function loss in both diabetic and nondiabetic kidney disease [18-20]. Any noncomparable effects of ACE inhibitors and ARBs may have resulted from variable blood pressure-lowering efficacy of different ARBs [18,21-23]. In addition, real-world evidence from a large observational study (including approximately two million people) found that there was no difference in efficacy of blood pressure control between ACE inhibitors and ARBs, but ARBs were better tolerated [24]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Other antihypertensive drugs — Other drugs, such as hydralazine, dihydropyridine calcium channel blockers, diuretics, and beta blockers, have not been shown to reverse intraglomerular hypertension (because they do not produce preferential efferent dilatation) and therefore may be less likely to protect against progressive glomerular injury (figure 1) [5,25]. Hydralazine and the dihydropyridine calcium channel blockers (eg, nifedipine, amlodipine), appear to produce prominent afferent or preglomerular arteriolar dilatation [5,6,26,27]. Decreased resistance at this site will allow more of the systemic pressure to be transmitted to the glomerulus, possibly producing no change or even an elevation in intraglomerular pressure, despite the associated reduction in systemic blood pressure. Increased efferent resistance also may occur, as the drug-induced vasodilatation leads to activation of the renin-angiotensin system. In comparison to nifedipine and amlodipine, nondihydropyridine calcium channel blockers (diltiazem and verapamil) are less potent vasodilators and have been shown to decrease the resistance at the efferent arteriole [6,25,28].

Studies using calcium channel blockers in experimental models of kidney disease have revealed conflicting results [6,26]: some have shown increasing proteinuria (consistent with a rise in intraglomerular pressure) and little protection against glomerulosclerosis [27], while others have shown benefit by mechanisms that may in part be independent of the intraglomerular pressure. (See "Secondary factors and progression of chronic kidney disease".)

OTHER ACTIONS OF ACE INHIBITORS — In addition to lowering the intraglomerular pressure, experimental studies suggest that the beneficial effect of renin angiotensin system (RAS) blockers may be related to a number of other factors (figure 2):

●Angiotensin II is a growth factor; therefore, diminishing its production may minimize glomerular hypertrophy which, by decreasing the capillary radius, can reduce the tension on the glomerular capillary wall [29,30]. This protective effect also may occur in extrarenal vessels, as the degree of vascular hypertrophy in hypertensive animals with kidney disease is less following therapy with an angiotensin-converting enzyme (ACE) inhibitor than with the triad of a thiazide diuretic, reserpine, and hydralazine [10]. Inhibition of local angiotensin II generation may be responsible for this vasculoprotective effect. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)

●Angiotensin II, either directly or via increased glomerular pressure, can enhance the release of extracellular matrix and collagen from mesangial and tubular cells, thereby promoting both glomerular and tubulointerstitial fibrosis [8,29-32]. This effect is mediated at least in part by enhanced release of transforming growth factor-beta, matrix proteins, platelet-derived growth factor, and plasminogen activator inhibitor-I [8,31,33-36]. Administration of an ACE inhibitor and/or angiotensin receptor blocker (ARB) decreases cytokine release, due most likely to a fall in glomerular pressure and/or reversal of the direct action of angiotensin II [33].

The ability of ACE inhibitors or ARBs to partially block the profibrotic effect of angiotensin II may be particularly due to their effect to decrease transforming growth factor-beta and plasminogen activator inhibitor-I levels (among others), and/or increase hepatocyte growth factor concentrations [37]. Due to these effects, ACE inhibitors and ARBs may help to reverse kidney sclerosis, as observed in multiple animal models of progressive kidney dysfunction [35,36,38]:

●An ACE inhibitor may directly improve the size selective properties of the glomerulus, thereby preventing the accumulation of macromolecules in the mesangium and a secondary increase in mesangial matrix production [39]. Diltiazem may have similar effects, while nifedipine worsens size selective properties [40]. Whether improvement in size-selective properties is related to or is independent of the associated reduction in intraglomerular pressure is not clear.

●Inhibition of angiotensin II production via ACE inhibition also lowers the release of aldosterone. (See "Secondary factors and progression of chronic kidney disease", section on 'Aldosterone'.)

●Due to decreased degradation, ACE inhibitors increase bradykinin concentrations, which may ameliorate kidney tubulointerstitial fibrosis. Support for this was provided by an animal model in which unilateral ureteral obstruction-induced interstitial fibrosis was significantly increased in bradykinin B2 receptor knockout mice [41]. Bradykinin may dampen fibrosis by increasing extracellular matrix degradation via enhanced metalloproteinase-2 and other enzymatic activity. A similar benefit by this mechanism would not be expected with an ARB, which does not increase bradykinin levels.

POSSIBLE ROLE OF ENDOTHELIN — Endothelin, a potent peripheral vasoconstrictor, has also been implicated in the progression of kidney failure, due in part to its ability to stimulate glomerular hypertrophy and extracellular matrix stimulation [42].

SUMMARY

●Renal hemodynamics and progressive kidney injury – Progression of a variety of chronic kidney diseases may be largely due to secondary hemodynamic and metabolic factors, rather than the activity of the underlying disorder. Antihypertensive therapy, particularly with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), is one important component of reducing risk of secondary kidney injury. (See 'Introduction' above.)

●Renin angiotensin system (RAS) blockers – Data in animal models concerning the efficacy of ARBs in protecting against progressive kidney disease are conflicting. Some studies have found that ARBs are as effective as ACE inhibitors, whereas other studies show they are inferior. However, while there may be differences in animal models, human studies show no difference in albuminuria reduction at similar blood pressure levels and no difference in slowing progression of kidney disease. (See 'Angiotensin receptor blockers' above.)

In addition to lowering the intraglomerular pressure, experimental studies suggest that the beneficial effect of RAS blockers may also be related to inhibition of other effects of angiotensin II, including glomerular hypertrophy and fibrosis. (See 'Other actions of ACE inhibitors' above.)

●Other antihypertensive agents – Hydralazine and dihydropyridine calcium channel blockers (eg, nifedipine, amlodipine) appear to produce prominent afferent or preglomerular arteriolar dilatation, and result in an elevation in intraglomerular pressure secondary to inhibiting renal autoregulation despite the associated reduction in systemic blood pressure. By comparison, nondihydropyridine calcium channel blockers (diltiazem or verapamil) are less potent afferent vasodilators and partially decrease efferent arteriole tone and only partially affect autoregulation. (See 'Other antihypertensive drugs' above.)