Risk Involved with Dual RAAS Blockade in Kidney Disease Source: Bakris GL. Dual RAAS blockade is desirable in kidney disease: Con. Kidney Int. 2010;78:546–549.

The data regarding the pharmacological blockade of renin– angiotensin–aldosterone system (RAAS) with angiotensin- converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) together leading to a reduction in albuminuria and proteinuria is evident. However, whether this is consistent with longterm renoprotection is not recognized. Several studies have documented that dual blockade of the RAAS results in an additional 20% reduction in albuminuria and are associated with renoprotection. f this finding is valid, then does it hold across the range of albuminuria, that is, >30 mg/day up to 10,000 mg/day, or is it relevant only in the macroalbuminuria range, that is, ≥300 mg/day? Based on this criterion, many studies are examining the correlation between microalbuminuria and kidney disease, and also the changes in both microalbuminuria and albuminuria in reference to blood pressure and other variables that can affect its genesis.

Microalbuminuria does not meet the criteria for a validated surrogate because of two reasons, – Its variability and lack of predictability. – Its lack of correlation with early pathological changes in the nephropathy, that is, mesangial expansion in diabetes. Thus the previous studies quoting it as a surrogate marker are invalid.

Data has also shown that changes in chronic kidney disease (CKD) outcome as reflected by albuminuria reduction by RAAS blockade are much more prognostic of CKD outcomes. According to the ABCD (Appropriate Blood Pressure Control and Diabetes) Trial, slowing of CKD progression results from an aggressive early blood pressure control, in spite of antihypertensive class, among the patients with microalbuminuria, hypertension and type 2 diabetes. Moreover, to obtain a significant data regarding validate surrogate, one would require over a decade of follow-up.

Changes in macroalbuminuria or proteinuria, that is, ≥300 mg/day of albumin with RAAS blockade, are more positive in the context of CKD outcomes, which is, doubling of creatinine and the need for dialysis, but they are all retrospective data from randomized clinical trials and none involving dual RAAS blockade.

A meta-analysis confirmed that the use of dual RAAS blockade results in an additional 20% reduction in albuminuria and this was in the context of an additional 3–5 mmHg reduction in systolic blood pressure. Trails have confirmed that a >30% reduction in proteinuria from baseline correlates with a slower decline in the glomerular filtration rate among those with advanced proteinuric nephropathy, therefore, the use of a dual RAAS blockade to provide an additional 20% reduction may be meaningful. However, the data supporting this statement is lacking. The results from the AVOID trial including advanced diabetic patients with proteinuric kidney disease were consistent with the findings of Kunz et al.

However in future, the three ongoing trials may get the solution for the query regarding dual RAAS blockade and CKD progression, and these trials will be running until 2012–2013. – The VA NEPHRON-D TRIAL—an ongoing doubleblind randomized, controlled trial within the veteran’s administration powered for CKD progression as the FDA definition and properly powered to address the issue. – The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints)—a large randomized doubleblind, placebo-controlled outcome trial in diabetic nephropathy patients. – HALT-PKD STUDY—trial of over 1,000 patients with polycystic kidney disease assessing the effects of dual RAAS blockade on kidney size over time.

Apart from reduced proteinuria, dual RAAS blockade also facilitates better blood pressure management. The dual RAAS blockade decreases the systolic blood pressure by about 3–5 mmHg, which is statistically vital, and epidemiologically appropriate to CKD results. Hence, it is not easy to evaluate the dual RAAS blockade in protecting the CKD progression, without a control group at equivalent levels of blood pressure. The risks of hyperkalemia linked with dual RAAS blockade were observed more in patients already on a maximal ACEI or ARB and a correct-dosed diuretic with an additional RAAS agent being added. Patients with an anticipated glomerular filtration rate 44.5 mEq/L were at maximum risk.

Conclusion Dual RAAS blockade has a promising role in advanced proteinuric nephropathy for additional reduction in 18 proteinuria; but in relation to CKD outcome, its contribution is not clear, because proteinuria is not a validated surrogate endpoint. Until further investigations are made, patients with higher levels of proteinuria should chose the combination of the RAAS blocking therapy. In addition, for proteinuria reduction, patients should be assessed for the risk of hyperkalemia, and should be considered for the use of a nondihydropyridine calcium antagonist combined with the single RAAS agent. Nondihydropyridine calcium antagonists reduce proteinuria; this is further reduced when the agent is combined with renin–angiotensin system blockers. This offers a secure and efficient option for patients with advanced nephropathic disease. Other than advanced proteinuric nephropathy, currently there are no data of any positive CKD outcome. Hence, dual RAAS blockade cannot be suggested for all CKD patients.

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