Elsevier

Diabetes & Metabolism

Volume 35, Issue 6, December 2009, Pages 425-430
Diabetes & Metabolism

Review
Optimal nephroprotection: Use, misuse and misconceptions about blockade of the renin–angiotensin system. Lessons from the ONTARGET and other recent trialsNéphroprotection optimale : usage, mésusage et erreurs conceptuelles à propos de l’inhibition du système rénine–angiotensine. Leçons tirées d’ONTARGET et d’autres essais récents

https://doi.org/10.1016/j.diabet.2009.05.003Get rights and content

Abstract

Results from the ONTARGET trial remind us that acute haemodynamically mediated renal dysfunction, triggered by low arterial pressure or volume depletion, can occur in high-risk cardiovascular patients (who usually have some degree of diseased intrarenal vessels) treated with renin–angiotensin system (RAS) blockers (especially in combination). However, nephroprotection could not be properly assessed in the trial, as the population was at low renal risk. Although albuminuria remains a useful marker in many patients, it can neither predict acute renal dysfunction nor replace end-stage renal disease (ESRD) as the endpoint in clinical trials. Recent trials using surrogate endpoints suggest that some RAS blockers (ACE inhibitors, angiotensin receptor blockers, the renin inhibitor aliskiren) may be more nephroprotective than others, but proving this requires comparing them (alone or in combination) in populations with identified renal disease (mainly diabetic nephropathy) and the use of hard endpoints. RAS-blocker dosages are critical: as some patients need much larger doses to decrease proteinuria than do others, the efficacy of a high-dose RAS blocker needs to be assessed in patients with persistent proteinuria. In patients with massive proteinuria despite maximum RAS-blocker dosages, combination RAS blockade should be considered by nephrologists, but will require close monitoring of renal function; also, the treatment needs to be withdrawn (at least temporarily) as soon as volume depletion or excessively low arterial pressure arises. In recent trials, lowering blood pressure towards values recommended by the current guidelines (130/80 mmHg) has reduced microvascular (lower levels of urinary albumin excretion) and macrovascular events in diabetic patients.

Résumé

Les résultats de l’essai ONTARGET nous rappellent que l’insuffisance rénale aiguë sous IEC et/ou ARA2 survient volontiers chez les patients à haut risque cardiovasculaire (ayant souvent une néphroangiosclérose) en hypoperfusion rénale par hypovolémie ou hypotension. Cet essai n’a pas permis de tester véritablement la néphroprotection des bloqueurs du système rénine-angiotensine (SRA), car le risque rénal des patients inclus était faible. L’albuminurie est un marqueur de risque chez de nombreux patients, mais est inutile pour prédire l’insuffisance rénale aiguë et ne remplace par les évènements durs (IRC terminale) dans les essais thérapeutiques. Des résultats d’essais thérapeutiques, fondés surtout sur des critères de substitution, suggèrent que certains bloqueurs du SRA (IEC, ARA2, inhibiteur de la rénine [aliskiren]) peuvent apporter une néphroprotection plus efficace que d’autres ; cependant, la preuve ne pourra être apportée que par l’utilisation de critères durs (dialyse chronique) chez des patients atteints d’une maladie rénale identifiée (néphropathie diabétique). La dose d’IEC ou d’ARA2 utilisée est un point critique : certains patients nécessitent une dose plus élevée que d’autres pour réduire la protéinurie : cela doit être testé pour chaque patient. L’association de bloqueurs du SRA doit être décidée par un néphrologue et restreinte aux patients qui présentent une protéinurie massive réfractaire aux hautes doses d’un bloqueur du SRA : le suivi étroit de la fonction rénale est indispensable, et ce traitement doit être arrêté (éventuellement temporairement) en cas d’hypovolémie (déplétion sodée ou pression artérielle trop basse). La baisse de la pression artérielle a permis la réduction de certains évènements microvasculaires (moins de microalbuminurie essentiellement) et macrovasculaires dans des essais thérapeutiques récents chez des patients diabétiques, renforçant ainsi les recommandations actuelles (pression artérielle < 130/80 mmHg).

Section snippets

Renal effects in the ONTARGET trial

ONTARGET was a large, randomized, double-blind trial aimed at answering two questions:

  • •

    Is the ARB telmisartan inferior to the ACEI ramipril in terms of preventing cardiovascular events in high-risk patients?

  • •

    Does combined blockade result in better cardiovascular protection than ramipril on its own [4]?

A total of 25,620 patients were randomized to receive either ramipril (10 mg/day), telmisartan (80 mg/day), or both (combined blockade), for five years. These patients were all high-risk

Harmful renal effects: lack of nephroprotection or acute renal dysfunction?

The population included in the ONTARGET trial was at high cardiovascular risk and low renal risk: the rate of ESRD was ∼0.4% during the 4.5 years of follow-up, and the annual GFR decline was similar to that observed in the general population (∼1 mL/min/year); this meant that nephroprotection could not be properly assessed in the trial. In addition, the risks of death (30 times more frequent) and of permanent discontinuation of the study drugs (around eight times more frequent) were much greater

What is the mechanism of acute renal dysfunction with combined blockade?

At this time, it is not known whether the renal effect of the drug combination was similar in patients with diabetes, hypertension, proteinuria or eGFR less than 60 mL/min/1.73 m2 [5]. In fact, the relative risk of the primary renal outcome (death, ESRD, doubling of serum creatinine) in each subgroup was reported, but not the relative risk of developing one of the components of the composite endpoint [5].

Sodium balance may be a critical issue. So far, there is no information on sodium intake

Nephroprotection: do ACEI and ARB have different properties?

The change in renal function was significantly faster in the telmisartan group (−4.1 mL/min/1.73 m2) than in the ramipril group (−2.8 mL/min/1.73 m2) in the ONTARGET trial. However, this finding did not translate into more chronic dialysis or doubling of serum creatinine with telmisartan vs ramipril. Again, there were few hard renal endpoints in the trial [5].

The apparent discrepancy between small changes in eGFR and the similar incidence of ESRD has already been noted in other trials in which

What is the optimal dosage for ACEI or ARB?

Recently, the concept of an ‘ultradose’ was presented in several reports. The results of IRMA2 indicated that a reduction in UAE was more effective with irbesartan at 300 mg/day than at 150 mg/day [20]. Later, when much higher doses of ARB were tested, it was found that candesartan and irbesartan at higher dosages were associated with greater UAE reductions in diabetic patients [21], [22]. However, from a renal point of view, the optimal dose of ARB (or ACEI) may differ from one patient to

Is urinary albumin excretion a surrogate marker of chronic renal failure?

In the ONTARGET trial, the increase in urinary albumin/creatinine ratio (UACR, 0.82 mg/mmol on average at baseline) appeared blunted in the telmisartan–ramipril group (ratio to baseline: 1.21) than in either the telmisartan (ratio to baseline: 1.24) or ramipril (ratio to baseline: 1.31) group — and yet, the combination blockade group had the poorest renal function outcome [5]. These results are in marked contrast to the findings reported in nondiabetic African-Americans with nephrosclerosis from

What can we do in daily practice for diabetic patients?

Maintaining strict blood pressure control is still recommended in patients with diabetes: strict vs less strict arterial blood pressure (144/82 vs 154/87 mmHg) was associated with lower incidences of stroke, heart failure, diabetes-related death and retinal panphotocoagulation (but not with significantly reduced rates of micro- or macroalbuminuria, or significant differences in serum creatinine, after nine years of follow-up) in the UKPDS [30]. In the ADVANCE study, reduction of blood pressure

Perspectives for the future

The ONTARGET results cannot be extrapolated to other dual RAS–blockade combinations. The nephroprotective properties of ACEI, ARB and the renin inhibitor aliskiren [42], [43] — used alone or in combinations — have to be compared in populations with identified renal disease, particularly those with proteinuric diabetic nephropathy. Such trials should also use hard renal endpoints (ESRD). Nevertheless, the proper use of UAE should not be abandoned, despite the fact that it does not help to

Conflicts of interest

None.

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