CORRESPONDENCE: LETTER TO THE EDITOR
Dual Renin-Angiotensin System Blockade and Kidney Disease
Hans-Henrik Parving, MD,
Barry M. Brenner, MD,
John J.V. McMurray, MD,
Dick de Zeeuw, MD,
Steven M. Haffner, MD,
Scott D. Solomon, MD,
Nish Chaturvedi, MD and
Marc A. Pfeffer, MD*
* Department of Medical Endocrinology, Righospitalet, Blegdamsvej 9, 2100 Ø, Copenhagen, Denmark (Email: hhparving{at}dadlnet.dk).
Based on the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) study dealing with renal outcomes (1), Messerli (2) concluded that albuminuria can no longer be regarded as a valid surrogate end point in renal disease and that dual renin-angiotensin system (RAS) blockade is dead until further notice. Since these interpretations have major importance, a meticulous analysis of the ONTARGET study findings is warranted.
The ONTARGET study was conducted in 25,620 participants with low risk of chronic progressive kidney disease, except the 263 patients wrongly enrolled with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2. The mean urinary albumin/creatinine ratio was 0.81 mg/mmol (7.2 mg/g), mean eGFR 73.6 ml/min/1.73 m2 with a sustained rate of decline <1 ml/min/year. The primary renal end point was a composite of any dialysis, doubling of serum creatinine, and death.
The need for dialysis was established arbitrarily with no pre-determined protocol, and data were assessed post-hoc with a questionnaire to all sites. Serum creatinine was measured locally, and the local methods were not calibrated to a standard. Change in creatinine method from Jaffe to enzymatic assays was not accounted for. Doubling of serum creatinine in major renal outcome trials are confirmed by a second measurement of serum creatinine, usually a month later than the first abnormal value (3,4). No such confirmatory measurements were carried out in the ONTARGET study. Single central measures of urinary albumin/creatinine ratio were carried out at baseline, at 2 years, and at the end of the study. Repeated determinations are generally applied in renal outcome trials due to huge variation in this ratio. The ONTARGET study was not powered to detect differences in renal outcomes.
The primary renal outcome was driven by death (approximately 84% of all the events). A secondary renal outcome: any dialysis or doubling of serum creatinine was similar with telmisartan (n = 189) and ramipril (n = 174), and more frequent with combination therapy (n = 212, p = 0.038 vs. ramipril, but p = NS vs. telmisartan). In 3 of 165 originally reported cases of dialysis (5), later information revealed that no dialysis took place. In 3 additional cases, no information could be obtained regarding acute (<2 months) or chronic dialysis (>2 months) (n = 61 [38.4%] dealt with acute dialysis for various reasons but not for hyperkalemia). Removing acute dialysis from the renal end point led to insignificant differences between the 3 groups. Treatment trials in chronic kidney disease never include acute dialysis in their primary end point (3,4,6,7). The number of patients in chronic dialysis was very low (0.36% to 0.40%) and nearly identical in the 3 arms.
The initial eGFR decline from baseline to 6 weeks was, as expected, significantly bigger during dual RAS blockade. This initial reversible hemodynamic phenomenon is well known, and mainly due to lowering of glomerular capillary hydraulic pressure (8,9). The sustained decline in eGFR (ml/min/year) from 6 weeks to final was 0.27 (ramipril), 0.44 (telmisartan), and 0.53 (combined) (p < 0.0001). These sustained reductions in eGFR are less than normally expected due to aging (0.6 to 1.1 ml/min/year).
All groups had a rise from baseline to final in albumin/creatinine ratio: 31% (ramipril), 24% (telmisartan), and 21% (combined). These findings are very surprising since previous studies dealing with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in kidney disease nearly always showed a reduction (10).
The ONTARGET study, investigating RAS blockade in a population with low risk for progressive kidney disease, applying insufficiently measured renal end points, confounded by death and acute dialysis, has resulted in inconclusive evidence and misinterpretation of the role of dual RAS blockade and importance of albuminuria as a valid surrogate end point for renal disease. We echo the final statement in the Lancet editorial on the ONTARGET study: "A properly done prospective trial in patients with advanced proteinuric chronic kidney disease is still needed to answer definitively the question about efficacy of combination therapy to block the RAS on progression of chronic kidney progression" (11). The proposed designed study is ongoing: the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study (12).
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1. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial Lancet 2008;372:547-553.[CrossRef][Web of Science][Medline]2. Messerli FH. The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point J Am Coll Cardiol 2009;53:468-470.[Abstract/Free Full Text] 3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes N Engl J Med 2001;345:851-860.[CrossRef][Web of Science][Medline] 4. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy N Engl J Med 2001;345:861-869.[CrossRef][Web of Science][Medline] 5. The ONTARGET Investigators Telmisartan, ramipril, or both in patients at high risk for vascular events N Engl J Med 2008;358:1547-1559.[CrossRef][Medline] 6. Lewis E, Hunsicker L, Bain R, Rhode R. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy N Engl J Med 1993;329:1456-1462.[CrossRef][Web of Science][Medline] 7. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria Lancet 1999;354:359-364.[CrossRef][Web of Science][Medline] 8. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease N Engl J Med 1994;330:877-884.[CrossRef][Web of Science][Medline] 9. Palmer BF. Renal dysfunction complicating the treatment of hypertension N Engl J Med 2002;347:1256-1261.[CrossRef][Web of Science][Medline] 10. Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal disease Ann Intern Med 2008;148:30-48.[Abstract/Free Full Text] 11. Sarafidis PA, Bakris GL. Renin-angiotensin blockade and kidney disease Lancet 2008;372:511-512.[CrossRef][Web of Science][Medline] 12. Parving H-H, Brenner BM, McMurray J, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design Nephrol Dial Transplant 2009;24:1663-1671.[Abstract/Free Full Text]
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