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Dr. Luis Ruilope
Dr. César Cerezo
Microalbuminuria is a CV risk factor in hypertensive patients. RAAS blockade is the elective treatment in patients with microalbuminuria, however chronic use does not rule out its potential presence. Tighter BP control in all cases, possible combination with Aliskiren (if study confirms efficacy superior to monotherapy), and spironolactone in cases of normal estimated glomerular filtration rates, may be alternative therapies until research uncovers whether reaching more complete inhibition of the RAAS is possible.
Co-existence of hypertension and diabetes increases the risk of renal and other target organ damage, and heads to greater incidence of cardiac events and mortality. When renal dysfunction starts to set in, proteinuria and microalbuminuria are predictors of development of renal and cardiovascular (CV) complications, -events and mortality (1,2,3). Therefore, detecting microalbuminuria, just as scientific guidelines recommend, will screen for renal disease even in its early stages. Strong evidence from the 1980’s on, have put forward that suppressors of the renin-angiotensin-aldosterone system (RAAS) may have specific renal protective properties. They are preferred agents both in monotherapy or as components of combination therapy (4). However, CV disease may still progress under chronic RAAS blockade (5), and therefore microalbuminuria, as predictor of both CV and renal disease, should continue to be monitored in patients who are under chronic RAAS blockade therapy.
Renal disease is a complication of diabetes and hypertension - which together make up the most common causes of chronic kidney disease (CKD) (6). Furthermore, there is growing evidence revealing the continuous relationship between worsening in renal function and CV disease and a sharp increase in risk of CV morbidity and mortality (7) (Fig. 1). The actual fact of composite interactions between CV disease, chronic kidney disease (CKD) and diabetes are becoming more widely accepted, however they are not completely understood, as yet (6). Stratification of CV risk as well, in hypertensive patients in particular, has also been considered increasingly relevant: markers suggesting preclinical renal damage are also able to detect CV disease, and moreover be used to predict CV morbidity and mortality. Initial clinical evidence of this was provided by observational studies in high risk patients. The HOPE trial (8), confirmed the predictive value of microalbuminuria in the development of overt nephropathy and CV mortality, with a similar prognostic capability than that of a previous coronary event, both in diabetic and non-diabetic patients. In parallel, importance of early detection of renal damage in the general population, as well as in patients with essential hypertension independently of blood pressure values, namely, by testing microalbuminuria, has been widely reported on. A great example of this was a collaborative meta-analysis of general population cohorts involving more than 1 million participants, demonstrated a direct relationship between renal dysfunction and CV risk: Estimated glomerular filtration rate <60 ml/ min/1.73 m2 and an albumin-to-creatinine ratio =1.1 mg/mmol (=10 mg/g)- the lower limit of high-normal albuminuria - were both independent predictors of mortality risk in the general population. An elevated estimated glomerular filtration rate and albumin-to-creatinine ratio each significantly increased mortality rate, without evidence of interaction between each measurement (9). Taken together, data demonstrating the composite interactions between CV disease, chronic kidney disease and diabetes, relevance of stratification of CV risk, and the predictive value of microalbuminuria in the development of overt nephropathy and CV mortality confirm the importance of microalbuminuria as CV risk factor in hypertensive patients.
Suppression of the RAAS is widely viewed as positive therapy to help improve renal outcome and especially helps diminish micro and macroalbuminuria. Both angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have renoprotective properties as has been shown in placebo-controlled, randomised trials and meta-analyses. They are able to reduce all-cause mortality, especially in patients with diabetic nephropathy (10,11,12). Thus, in patients with increased excretion of albumin in urine, RAAS blockade is essential, both to obtain controlled blood pressure (BP) and reduced albuminuria (3) which will in turn protect renal function and delay development of end-stage renal disease. That is especially the case in patients with macroalbuminuria (12,13). In parallel, the protective function of RAAS suppression in overt CV disease was shown in patients with heart failure, post-myocardial infarction and in individuals with high global CV risk, and is especially suited to subjects with CV and renal disease. Added to the extensively proven antihypertensive effectiveness of RAAS suppressors (3) these findings have lead to large utilisation of ACEi and ARBs, mainly in the premature stages of the CV continuum, when only a clustering of risk factors accompany BP elevation, without evidence of target organ damage or established CV disease.
We have recently published a retrospective study on the evolution of albuminuria in a cohort of 1433 patients (mean age 60.5 years; 50.3% male), that were admitted into our Hypertension Unit (14). Patients had in common previous therapy with an ACEi or an ARB, at appropriate doses, alone or in combination with other antihypertensive drugs, for a minimum of two years prior to arrival in our Center, and they were followed for three years with maintained RAAS suppression.
a) Microalbuminuria When patients first arrived at our Unit, they presented with a high prevalence of albuminuria: 16.4% microalbuminuric and 4% macroalbuminuric. Even though patients received optimal therapy during the three years of follow-up, prevalence of albuminuria during that time increased. b) Relation to CV disease 15.8% of patients presented previous CV disease at baseline and 4.6% developed new CV events
c) De novo microalbuminuria appeared in a further 16.1% of normoalbuminuric patients while an additional 1.0% developed macroalbuminuria.
Conclusion: Long-term RAAS suppression does not appear to reliably prevent progression and evolution of albuminuria both in diabetic and non-diabetic hypertensive patients. Incomplete inhibition of the RAAS may be responsible for the residual organ damage and event rates observed hypertensives, diabetics, chronic kidney disease and heart failure patients treated with ACEi or ARBs on monotherapy. Moreover baseline renal function, glycemic control and severity of hypertension are factors independently related to increased urinary albumin excretion. Even in chronic RAAS suppression, albuminuria remains a powerful predictor of cardiovascular events. In view of improving these patients’ outcomes, further research to determine whether RAAS suppression capacity is at its maximum or if it can be further enhanced is warranted.
1- De Jong PE, Gansevoort RT, Bakker SJ. Macroalbuminuria and microalbuminuria do both predict renal and cardiovascular events with similar strength? J Nephrol 2007; 20: 375-380. 2- Sehestedt T, Jeppesen J, Hansen TW, Wachtell K, Ibsen H, Torp-Pedersen C, et al. Risk prediction is improved by adding markers of subclinical damage to SCORE. Eur Heart J 20 10; 31: 883-891. 3- Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–1187. 4- Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M, et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Eng J Med 1985; 313: 1617-1620. 5- Gustafsson F, Segura J, Ruilope LM. How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta blockers for hypertension, diabetes or coronary disease? J Hypertens 2010; 28: 1595-1598. 6- Bakris GL, Ritz E; World Kidney Day Steering Committee. The message for World Kidney Day 2009: hypertension and kidney disease – a marriage that should be prevented. J Hypertens. 2009;27:666–669. 7- Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS GROUP. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225-232. 8- Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253-259. 9- Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010; 375, 2073–2081. 10- Strippoli GF, Craig M, Schena FP, Craig JC. Antihypertensive agents for primary prevention of diabetic nephropathy. J Am Soc Nephrol. 2005;16:3081–3091. 11- Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH 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. 12- Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al.; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Eng J Med 2001; 345:851–860. 13- Cerezo C, Ruilope LM, Segura J, Garcia-Donaire JA, de la Cruz JJ, Banegas JR, Waeber B, Rabelink TJ, Messerli FH. Microalbuminuria breakthrough under chronic renin-angiotensin-aldosterone system suppression. J Hypertens. 2012 Jan;30(1):204-209. 14- Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869. 15- ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575-1585. 16- Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al.; ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in Type 2 diabetes. N Engl J Med 2011; 364: 907-917. 17- ONTARGET Investigators, 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. 18- Duggan ST, Chwieduk CM, Curran MP. Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension. Drugs 2010; 70: 2011-49. 19- Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433-2446. 20- Ferrario CM. Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin-angiotensin-aldosterone system: antihypertensive effects and benefits beyond BP control. Life Sci 2010; 86:289-99. 21- Engbaek M, Hjerrild M, Hallas J, Jacobsen IA. The effect of low-dose spironolactone on resistant hypertension. J Am Soc Hypertens 2010; 4: 290-4.
Figure 1. Annual risk of cardiovascular (CV) death in patients with type 2 diabetes mellitus and different degrees of nephropathy in the UKPDS. Micro: microalbuminuria; Macro: macroalbuminuria; Elev creat: elevated plasma creatinine or renal replacement therapy (7).
Figure 2. Development of new-onset albuminuria among hypertensive patients according to previous cardiovascular events (13).
Correspondence: César Cerezo Hypertension Unit. Hospital 12 de Octubre Av. Córdoba s/n 28041 Madrid. Spain T: 34913908198 F: 34913908035 Declaration of interest: None declared.
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