ReviewOptimal 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
Section snippets
Renal effects in the ONTARGET trial
ONTARGET was a large, randomized, double-blind trial aimed at answering two questions:
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Is the ARB telmisartan inferior to the ACEI ramipril in terms of preventing cardiovascular events in high-risk patients?
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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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Cited by (7)
American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan—2022 Update
2022, Endocrine PracticeCitation Excerpt :Combination therapy with an ACE inhibitor and an ARB or with a renin inhibitor added to another RAAS-blocking agent does not prolong survival or prevent progression of CKD.263,440,441 In persons with advanced CKD (G3b and higher), combination therapy increases the risk of hyperkalemia and AKI and is therefore not recommended.263,441,442 On top of the prevailing standard of care with an ACE inhibitor or an ARB, there has been a major upsurge in new highly effective therapies for people with T2D to reduce risks of DKD or CKD in DM progression, kidney failure, HF, ASCVD, and death for some agents.
American Association of Clinical Endocrinologists and American College of Endocrinology - Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015
2015, Endocrine PracticeCitation Excerpt :Patients with CKD are at risk for drug toxicity and acute kidney injury. Antihyperglycemic therapies should be modified to reduce excessive drug exposure and hypo-glycemia (276 [EL 3; CSS]). Many other drugs should be avoided or used with caution in patients with CKD.
FK506 ameliorates podocyte injury in type 2 diabetic nephropathy by down-regulating TRPC6 and NFAT expression
2015, International Journal of Clinical and Experimental PathologyNew insight into the molecular drug target of diabetic nephropathy
2014, International Journal of EndocrinologyPersistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats
2010, American Journal of Physiology - Renal PhysiologyAccord-lipid and accord-eye: Towards a new positioning of fenofibrate in the management of type 2 diabetes
2010, Revue Medicale de Liege