Hypertension 1996 : One Medicine, Two Cultures

ACE-inhibitors in renal hypertension

S. Di Giulio*, C. Cherubini, P. De Paolis, A. Friggi, L. Meschini, M. Rosa, F. Stortoni
Nephrology and Dialysis - G.B. Grassi Hospital - Rome Ostia
*Specialized School of Nephrology – Rome University Tor Vergata

The reduced development of renal impairment brought about by ACE-inhibitors seems to be by now confirmed by several trials and clinical studies. The inhibitors of the enzyme responsible for the conversion of angiotensin I to II in uraemic rats reduce proteinuria and glomerular sclerosis. The beneficial effect on the decrease of albuminuria and, at the same time, on the development of renal impairment in diabetic patients (1.7) with kidney disorders has been known for a few years. Recent controlled studies were primarily aimed at ascertaining this positive effect of ACE-inhibitors on the development of renal impairment in all other renal diseases (2, 3, and 4). A secondary but equally important aim is to establish whether the ability to preserve the kidney's function generally depends upon better control of hypertension or rather upon specific factors related to the role of angiotensin II and, subsequently, to its drug-related inhibition. In the past, the kidney-protective effect of ACE-inhibitors had been described in renal diseases involving intercapillary build-up of IgA (Berger's disease) (5). Several studies also compared different anti-hypertensive drugs: Zucchelli (8) and colleagues did not highlight any significant difference between calcium-antagonists and ACE-inhibitors in preventing the development of uraemigenic renal diseases, even though the anti-hypertensive action generally affected the treated patients positively. The most recent and substantial study that clearly highlighted the primary role of ACE-inhibitors in reducing the pace of renal impairment progression is the AIPRI study. (9). In the AIPRI (ACE Inhibition in the Progression of Renal Impairment) study, each patient from any of 49 different hospitals, with creatinine blood levels ranging from 1.5 to 4 mg/dl, was submitted to preliminary assessment. The patients included in the study underwent a nephrologic evaluation for approximately 3 months, during which nutritional parameters, arterial pressure value, and the renal disease's activity signs were monitored. Later, only patients affected by reported chronic renal impairment (due to renal disease, development speed, treatment compliance, and homogeneity of co-morbidity factors, etc.) were included in the study.
Patients were followed up for a 3-year period, during which they received an ACE-inhibitor (benazapril) alone or along with other anti-hypertensive drugs. The treated patients were compared with a group that only received a placebo. The study included 600 patients and. in the light of measurable effects, it further confirmed that, below this number of individuals examined and over shorter periods, no statistical evaluation of the ACE-inhibitor’s effects on the development of renal impairment is allowed. Effects are obviously more visible the quicker the progressive development of each renal disease considered; on the other hand slowly developing renal diseases (nephroangiosclerosis and polycystic disease) should be followed up for a longer period. In the AIPRI study the main benefits were identified as a reduced pace of development of diabetes-related renal diseases and, generally, of glomerular diseases, while patients affected by interstitial nephritis and other renal diseases (e.g. of a genetic kind) did not even reach the established “end-points”. Longer follow -up periods would probably have allowed drawing conclusions in these cases as well. Both in mild and in moderate cases, the factor hampering renal impairment development was highlighted: this effect was even clearer the earlier the therapy was issued with respect to the onset of the kidney disease. Since the monitoring of arterial hypertension had previously been ensured, before assigning patients to ACE-inhibitor treatment, the anti-hypertensive action could be separated from the action specifically preventing the progression of renal impairment. This methodological precaution was only taken in few studies. In the AIPRI study, hypertensive patients subject to ACE-inhibitor intake experienced a slower progression of uraemia, both when pressure was carefully monitored and when a moderate hypertension persisted in spite of ACE-inhibitor intake. No positive effects were observed, instead, in spontaneously normotensive patients treated compared to placebo controls. As expected, the placebo group showed an arterial pressure value approximately 6 mmHg higher compared to the ACE-inhibitor group, although they received a higher number of anti-hypertensive drugs. However, the protective effect observed in 53% of ACE-inhibitor cases showed a slight decrease (to 38%) when data were adjusted according to pressure values. This point out to the considerable protective effect ensured by ACE-inhibitors even when the pressure effects of the drug were disregarded. ACE-inhibitor patients also reported a decrease in proteinuria, which appeared greater the higher the value of baseline proteinuria; this did not exclude that, even in case of moderate proteinuria, the action of a uraemia reduction was not visible, but this was evident in fewer patients. This figure may probably be interpreted by taking proteinuria as an indicator for development rather than as a pathogenic factor per se. However, proteinuria is known to represent a “glomerular traffic” element with subsequent activation of mesangium cells involved in controlling this protein's flow. The progression to sclerosis is experimentally proportional to the extent of this traffic and to the subsequent mesangium activation. However the threshold of sensitivity to proteinuria was lower (1 g/day) compared to the 3 g/day highlighted by other studies. In other terms, the beneficial effects of ACE-inhibitors were also observed in non-nephrotic patients. This consideration diminishes the importance of the possible beneficial effects produced by a change in renal haemodynamics as observed after hypo-albuminaemia adjustment. The poor protective effect observed in polycystic patients may not be attributed to the poor sensitivity of this renal disease to the renin-angiotensin system that, instead, is strongly stimulated in the polycystic disease. Along with the slow progression of uraemia in the polycystic disease, the time of the disease’s onset should probably be considered too, since it seems to occur much earlier than the time of diagnosis compared to other renal diseases. These comments should be more detailed with respect to the polycystic disease in order to anticipate the introduction of ACE-inhibitors even if no arterial hypertension and/or renal impairment is observed. On the other hand it should be remembered that even kidney-protection obtained through low-protein diets (10) had turned out very poor in the polycystic disease. Many mechanisms are assumed to account for this protective effect of ACE-inhibitors: reduced stress on the incorrectly called glomerular capillaries that are, actually, arteriolar. Even the proliferation of glomerular cells and cells involved in the mechanism of fibrosis is significantly and directly reduced by ACE-inhibitors.
Many patients included in the AIPRI study reported increased creatinine values at first, followed by a reduced increase speed compared to placebo patients. This trend, observed under ACE-inhibitor treatment, is probably the reason for some perplexity which limited the use of this group of drugs in the past, mostly set aside for “aesthetic” reasons linked to worsening blood values. The importance of this AIPRI study is linked to its ability to finally demonstrate this relative improvement of renal impairment progression in all renal diseases and the fact that this initially increased creatinine level does not bring about functional renal impairment, but rather only an adjustment of relations between renal plasma flow and glomerular filtration.
The increased creatinine level, in fact, results from a haemodynamic readjustment that, indeed, reduces hyperfiltration conditions while providing long-term kidney protection. Customary contraindications obviously remain in case of stenosis of renal arteries, due to the risk of thrombosis, especially in transplanted patients. On the other hand, the acute renal impairment linked to ACE-inhibitor intake is much more frequently related to an underestimated ischaemic damage, probably intensified by a change in the renal plasma flow due to the ACE-inhibitor.
Conclusion: ACE-inhibitors perform a kidney protective action on the progression of renal impairment in uraemigenic renal diseases. This effect is associated with but independent of an improved control of arterial hypertension enabled by the addition of this drug to treatment. The kidney-protection effect of ACE-inhibitors is more evident the higher proteinuria values and the quicker the disease initially develop. ACE-inhibitors are active in all renal diseases, even though they are particularly effective in glomerular forms rather than in polycystic diseases and nephroangiosclerosis.

References

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