Department of Nephrology and Hypertension, Medical School Hannover, Germany
Correspondence to Jan Menne, Medical School Hannover, Department of Nephrology and Hypertension, Carl NEuberg Str. 1, 30625 Hannover, Germany. E-mail: firstname.lastname@example.org
There is ample epidemiological evidence to suggest that albuminuria is a powerful and independent predictor of progressive kidney and cardiovascular disease in both the general population and in patients at high cardiovascular risk. The association of albuminuria with clinical events is strong and continuous, actually at any measurable amount of albumin, even well below the microalbuminuric range [1,2]. Furthermore, changes in albuminuria over time have been also clearly shown to predict clinical outcomes. Approximately 4 years after baseline, urinary albumin excretion (UAE) was measured again in a proportion of the initial cohort of the Prevention of REnal and Vascular ENdstage Disease (PREVEND) Study. Compared to participants with consistently low UAE, those who progressed from low to high UAE had a significantly higher risk for subsequent cardiovascular complications . Similarly, in a post-hoc analysis of the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant patients (TRANSCENT) and ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint (ONTARGET) trials, a greater than or equal to two-fold increase in albuminuria from baseline to 2 years, was associated with a 30% increase in cardiovascular events, a 40% increase in renal events and a 50% increase in mortality during the following 3 years. Conversely, decreases in albuminuria by more than 50% were associated with a 15% reduction in all-cause mortality . Thus, albuminuria reduction is a reasonable therapeutic strategy to reduce risk and improve outcomes.
Renin–angiotensin–aldosterone system (RAAS) blockers exhibit dose-dependent and blood pressure-lowering independent antiproteinuric actions and are therefore recommended as first-line treatment in the setting of hypertension and albuminuria . In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study it was demonstrated that the combination of an ACE inhibitor with a diuretic was superior to a combination of an ACE inhibitor with a calcium channel blocker (CCB) with regard to regression of albuminuria and prevention of the development of new albuminuria . However, it is unclear what to do in patients that are already treated with a RAAS inhibitor and a diuretic and still are hypertensive and have albuminuria. Should we add a third antihypertensive, preferentially a CCB, or should we stick with the two drug combinations? The study of Kojima et al. reported in this issue of the Journal helps to answer this practical question . They treated 80 patients with diabetes and albuminuria with a combination of 40 mg telmisartan and as a diuretic 1 mg trichlormethiazide for 3 months. Forty patients who still had albuminuria (>30 mg/g creatinine) and blood pressure between 130 and 179 mmHg (average around 142 mmHg) were randomly assigned to double the dose of telmisartan or to receive 5 mg amlodipine. The target blood pressure was below 130/80 mmHg and the primary endpoint was the reduction of urinary albumin levels after 6 months. Both treatments reduced blood pressure to a similar degree; patients within the intensified RAAS group blockade showed a significantly higher reduction in albuminuria . However, two limitations needs to be considered before concluding that up-titration of a RAAS inhibitor is the preferred treatment option in patients on a dual antihypertensive medication with a RAAS inhibitor and a diuretic. First of all, the telmisartan dose (40 mg o.d.) used during the run-in phase is neither in Europe nor in Japan the maximum recommended dose of 80 mg. Even after considering that the Japanese study population was slim and relatively small compared to a European population, the study would have been of greater clinical importance if 80 mg would have been used during the run-in phase and the dose would have been doubled to 160 mg. Secondly, the study of Kojima et al. should be interpreted by considering the underlying pathophysiological mechanisms of albuminuria, by distinguishing the hemodynamic actions of the various antihypertensive agents on the glomerular filtration rate (GFR) from structural irreversible renal damage and, most importantly, by keeping in mind that until now, no study has directly evaluated whether pursued albuminuria reduction translates into fewer cardiovascular events.
The well known implication of the RAAS system in the pathogenesis of cardiovascular disease and the recognition that especially low-grade albuminuria is more an early marker of widespread vascular damage and less an indicator of renal disease, had an impact on the management of hypertension. Higher-than-conventional dosages or combinations of RAAS blockers were used in order to increase the inhibition of the RAAS system and to potentiate their beneficial pleiotropic effects. Nevertheless, short-duration studies targeting only albuminuria have not provided uniform but rather conflicting results (Table 1). Higher doses of irbesartan decreased microalbuminuria significantly without additional blood pressure reductions, whereas dual RAAS blockade with irbesartan and ramipril did not reduce albuminuria more effectively than ramipril alone, despite significant reductions in blood pressure. Furthermore, the combination of candesartan and lisinopril reduced microalbuminuria more effectively than the respective monotherapies, but the results were mainly blood pressure-dependent. On the contrary, the combination of lisinopril with valsartan provided a significantly better reduction in microalbuminuria than lisinopril or valsartan alone, whereas differences in blood pressure did not achieve statistical significance. Clearly, many of these discrepant findings can be attributed to the known high intra-individual variability of low-grade albuminuria and the different methods used to assess the urinary albumin excretion rate, and also the relatively small number of patients included in most studies. Further inherent drawbacks were the short duration of follow-up and the targeting of a surrogate and not uniformly accepted biomarker of cardiovascular disease without putting emphasis on hard clinical endpoints. This issue has been addressed and solved in the ONTARGET study, were combination therapy did not reduce cardiovascular complications compared to monotherapy and this happened despite significant reductions in microalbuminuria .
Different drugs might affect GFR differently over time. RAAS blockers dilate preferentially the efferent vessel and reduce GFR functionally in the short term, whereas the long-term preservation of GFR is attributed primarily to structural renal changes. Dihydropyridine calcium channel blockers induce an increase in GFR through their vasodilatory actions mainly on the afferent vessel (also the case in the Kojima study). Such acute hemodynamic changes in GFR could affect albuminuria temporarily. Reduction in glomerular hyperfiltration would be expected to reduce albuminuria and vice versa. But again, the comparative effects of combination therapy on hard clinical endpoints were practically unknown until the publication of the ACCOMPLISH study. In that study the combination of an ACE blocker and a diuretic was inferior to the combination of an ACE blocker and a CCB in preventing cardiovascular complications and even in preserving renal function, despite being superior in preventing and reducing microalbuminuria .
The above data exemplify once again the huge differences between surrogate markers and hard clinical endpoints and highlight the fact that, although (micro-)albuminuria is a valuable biomarker, it requires further investigation. The effects of the various antihypertensive agents in the prevention of new-onset albuminuria and in reducing already established albuminuria are mainly blood pressure-driven. The higher the initial blood pressure levels the better the response to therapy. Nowadays, there exists no rationale to recommend targeting microalbuminuria beyond and above blood pressure control in hypertensive patients with type 2 diabetes. The results of the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study should remind us that such an approach can have detrimental effects, at least under specific clinical conditions. In ROADMAP, excellent blood pressure control, well below the recommended targets, was achieved in both treatment groups. Olmesartan prevented the development of albuminuria but led to an increased rate of fatal cardiovascular events in patients with established cardiovascular disease, probably because of excessive reduction in blood pressure .
The work of C.C. and J.M. is supported by the European Union (HEALTH-2011–278249-EU-MASCARA).
Conflicts of interest
J.M. has received honoraria for lectures and travel support from Daiichi Sankyo; C.C. has no conflict of interest.
1. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380:1662–1673.
2. Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, Ohkubo T, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet 2012; 380:1649–1661.
3. Brantsma AH, Bakker SJ, de Zeeuw D, de Jong PE, Gansevoort RT. Extended prognostic value of urinary albumin excretion for cardiovascular events. J Am Soc Nephrol 2008; 19:1785–1791.
4. Schmieder RE, Mann JF, Schumacher H, Gao P, Mancia G, Weber MA, et al. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol 2011; 22:1353–1364.
5. Menne J, Chatzikyrkou C, Haller H. Microalbuminuria as a risk factor: the influence of renin-angiotensin system blockade. J Hypertens 2010; 28:1983–1994.
6. Bakris GL, Sarafidis PA, Weir MR, Dahlof B, Pitt B, Jamerson K, et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet 2010; 375:1173–1181.
7. Kojima M, Ohashi M, Dohi Y, Kimura G. Titration of telmisartan, but not addition of amlodipine, reduces urine albumin in diabetic patients treated with telmisartan–diuretic. J Hypertens 2013; 31:186–191.
8. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559.
9. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364:907–917.
10. Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int 2005; 68:1190–1198.
11. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and noninsulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 321:1440–1444.
12. Bakris GL, Ruilope L, Locatelli F, Ptaszynska A, Pieske B, de Champlain J, et al. Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007; 72:879–885.
13. Menne J, Farsang C, Deak L, Klebs S, Meier M, Handrock R, et al. Valsartan in combination with lisinopril versus the respective high dose monotherapies in hypertensive patients with microalbuminuria: the VALERIA trial. J Hypertens 2008; 26:1860–1867.
14. Bakris GL, Toto RD, McCullough PA, Rocha R, Purkayastha D, Davis P. Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study. Kidney Int 2008; 73:1303–1309.