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The use of ACE inhibitors and ARBs in severe chronic kidney disease: point--counterpoint.

As health care providers practising evidence-based medicine, we must continually keep current on new literature in our field. Oftentimes, we are left with the daunting task of deciphering the practical implications of seemingly contradictory messages. In particular, there has been much debate regarding the use of inhibitors of the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in the severe chronic kidney disease (CKD) patient population.


ACE inhibitors act within the RAAS by inhibiting the conversion of angiotensin I to angiotensin II and, thereby, opposing its physiologic effects on aldosterone secretion, arteriolar vasoconstriction, and water and salt retention. ARBs act at the receptor level to produce a similar effect (Saseen & Carter, 2005).

For a number of years, caution has been used when prescribing inhibitors of the RAAS in patients with CKD due to their cited potential to decrease glomerular filtration rate (GFR), increase serum creatinine levels and result in hyperkalemia (Morimoto, et al., 2004). Ironically, patients with CKD were initially excluded from many of the clinical trials that led to the discovery of ACE inhibitors' renoprotective effects (Maschio, et al., 1996). Some literature now suggests that these agents remain renoprotective regardless of the patient's stage of kidney disease (Hou, Zhang, & Zhang, 2006; Ruggenenti, Perna, Remuzzi & Gruppo Italiano di Studi Epidemiologici in Nefrologia, 2001). This controversy may result in these medications being withheld from patients who may benefit from their use or cause them to be used when they may not be appropriate.

This article will attempt to address both sides of the controversy on the use of inhibitors of the RAAS in the severe CKD population.


Inhibitors of the RAAS have exhibited adverse events such as hyperkalemia and acute renal failure, particularly in high-risk patient populations. As a result of their side effect profile, health professionals may show hesitancy in prescribing these medications to these patients.

In 2007, a Swedish study of 551 hospitalized patients sought to retrospectively categorize the speed of development of hyperkalemia (defined as serum potassium of [greater than or equal to] 5.0 mmol/L) in patients with different known risk factors. The authors noted development of hyperkalemia was quickest with the use of potassium supplements (adjusted OR 3.386; 95% CI 2.251 to 5.091, p<0.001), followed by severe renal impairment (OR 3.119; 95% CI 2.007 to 4.850; p< 0.001), use of ACE inhibitors or ARBs (OR 2.642; 95% CI 1.742 to 4.006; p< 0.001), use of potassium-sparing diuretics (OR 2.065; 95% CI 1.310 to 3.254; p = 0.002), and diabetes mellitus (OR 1.525; 95% CI 1.005 to 2.313; p = 0.047). While potassium supplements and potassium-sparing diuretics demonstrated a dose effect, this was not found with ACE inhibitors and ARBs. Moreover, the authors found that hyperkalemia developed most quickly when patients had two or more of the above risk factors (Indermitte, Burkolter, Drewe, Krahenbuhl & Hersberger, 2007).

A 2004 retrospective cohort study evaluating risk factors for adverse drug events associated with ACE inhibitors found factors such as hyperkalemia and renal impairment to be reasons for discontinuation of the medication. In this study, 2,225 outpatients, administered ACE inhibitors, were followed for one year for adverse events. The authors found that 19% of the initial group discontinued ACE inhibitor therapy due to adverse events. Patients with serum creatinine of [greater than or equal to]141 mmol/L were more likely to stop therapy with ACE inhibitors due to renal dysfunction (HR 4.7; 95% CI: 1.5 to 12.7) and hyperkalemia (HR 10.9; 95% CI: 3.1 to 39.0) (Morimoto et al., 2004).

Hsu, Bates, Kuperman & Curhan (2001), in their study, "Blood pressure and angiotensin converting enzyme inhibitor use in hypertensive patients with chronic renal insufficiency," sought to investigate actual clinical management of hypertension in 3,089 ambulatory patients with CKD by using medical record information from a Massachusetts hospital. They found that physicians were less likely to prescribe ACE inhibitors in patients with moderate CKD (defined as a creatinine clearance of 21 to 40 mL/min) than in patients with CrCl > 60 mL/min (Hsu et al., 2001). The authors suggest that the patients in this study were frequently treated by a practitioner other than a nephrologist who may have exercised more caution in prescribing ACE inhibitors in this patient population.


Literature suggests that RAAS inhibitors offer greater benefits than harm in both nondiabetic and diabetic patients.

In 2001, Ruggenenti et al. sought to determine the risks versus benefits of using ACE inhibitors in patients with severe CKD. In this analysis, 322 patients with nondiabetic chronic kidney disease at varying stages of disease were placed into one of three groups (described as 'tertiles') based upon their initial GFR, or baseline kidney function. Patients' basal GFR progressively increased from lowest, middle to highest tertile. Within each tertile, patients were randomly assigned to either ramipril or conventional treatment. The rate of GFR decline and the incidence of end stage renal disease (ESRD) were compared between the two treatment groups in each tertile. As compared to conventional treatment, ramipril decreased the change in GFR by 22%, 22% and 35%, and the incidence of ESRD by 33% (p< 0.05), 37% and 100% (p< 0.01) respectively in the lowest, middle and highest tertiles. The authors concluded that the progression of CKD and a patient's response to ACE inhibitors did not depend on the patient's stage of kidney disease. They suggest that the renoprotective effects are maximized when ACE inhibitor therapy is started earlier in the course of the disease (i.e., GFR > 50 ml/min), but that therapy should be offered to all patients with kidney disease, even in those with filtration rates between 10 and 30 ml/min (Ruggenenti et al., 2001).

In 2006, Hou et al. (2006) validated these results. Four hundred and twenty-two patients with nondiabetic severe CKD were placed into one of two groups based upon their baseline serum creatinine levels. Patients in group one (serum creatinine between 133 to 265 mmol/L) received 20 mg of benazepril per day and patients in group two (serum creatinine between 274 and 442 mmol/L) were randomly and equally assigned to receive 20 mg of benazepril per day or placebo and were followed for 3.4 years. The study's primary outcome included a doubling of serum creatinine level, ESRD, or death. Secondary outcomes included changes in urine protein levels and the rate of progression of kidney disease. The authors found a statistical 43% decrease in the risk of the primary outcome in group two, as compared to placebo. They concluded that the ACE inhibitors were renoprotective in nondiabetic patients with advanced kidney disease (Hou et al., 2006).

A 2008 Cochrane Review sought to explore the use of ACE inhibitors and ARBs in preventing the progression of kidney disease in the diabetic patient population. The review included 49 studies with 12,067 diabetic patients at all stages of kidney disease. It included studies that compared ACE inhibitors or ARBs to placebo and studies that directly compared ACE inhibitors and ARBs. The authors found that both ACE inhibitors and ARBs were beneficial in terms of significantly improving renal outcomes (ESKD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) (Strippoli, Bonifati, Craig, Navaneethan & Craig, 2006). In fact, when compared to placebo, ACE inhibitors used at maximum tolerable dose prevented death in patients with diabetic kidney disease (RR 0.78; 95% CI 0.61 to 0.98; NNT 28). These mortality data were not found with ARBs. Thus, even though both ACE inhibitors and ARBs prevent the progression of nephropathy, the authors suggest that ACE inhibitors should be employed as first-line therapy since they are less expensive than ARBs and have proven survival benefit when used at their maximum tolerable dose.


It appears that ACE inhibitors and ARBs may be used safely and effectively in both diabetic and nondiabetic patients with moderate to severe CKD when monitored appropriately. Based upon the most current literature, patients who may benefit the most include patients with diabetes, as these patients would be at high risk of kidney and cardiovascular complications, and patients experiencing proteinuria with CKD. This recommendation is also consistent with the clinical practice guidelines of the National Kidney Foundation Disease Outcomes Quality Initiative (2002) and the Canadian Hypertension Education Program (2008). Caution should be exercised when using these therapies in patients with severe CKD concomitantly using one or a combination of the following medications: ARBs, non-steroidal anti-inflammatory agents (NSAIDs), potassium supplements, and potassium-sparing diuretics.

As health care providers, we should be aware of the unlikely possibility of hyperkalemia and/or acute renal failure, especially in high-risk patients, and consider the following measures in effort to avoid these occurrences (Saseen & Carter, 2005).

(1) ACE inhibitors and ARBs may be initiated at the lowest possible dose and titrated up according to the treatment goal. In fact, it may be beneficial to use a short-acting agent initially, followed by conversion to a longer-acting agent with titrations;

(2) Serum concentrations of creatinine and potassium should be obtained at baseline and remeasured about a week following the initiation of therapy with ACE inhibitors or ARBs;

(3) Acute renal failure may be prevented by transiently discontinuing preordered diuretics upon initiating ACE inhibition or ARB therapy. In particular, special caution should be exercised in the use of potassium-sparing diuretics during concomitant therapy with ACE inhibitors, as this class of diuretics inherently increases serum potassium levels.

(4) In a further effort to prevent hyperkalemia, patients may be counselled on the importance of limiting intake of potassium-rich foods.


Canadian Hypertension Education Program. (2008). Management and prevention of hypertension in Canada. Retrieved from

Hou, F., Zhang, X., Zhang, G.H., Xie D., Chen, P.Y., Zhang, W.R., et al. (2006). Efficacy and safety of benazepril for advanced chronic renal insufficiency. New England Journal of Medicine, 354, 131-40.

Hsu, C., Bates, D., Kuperman, G.J., & Curhan, G. (2001). Blood pressure and angiotensin converting enzyme inhibitor use in hypertensive patients with chronic renal insufficiency. American Journal of Hypertension, 14, 1219-1225.

Indermitte, J., Burkolter, S., Drewe, J., Krahenbuhl, S., & Hersberger, K.E. (2007). Risk factors associated with a high velocity of the development of hyperkalemia in hospitalized patients. Drug Safety, 30(1), 71-80.

Maschio, G., Alberti, D., Janin, G., Locatelli, F., Mann, J.F., Motolese, M., et al. (1996). Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. New England Journal of Medicine, 34, 939-945.

Morimoto, T., Gandi, T., Fiskio, J., Seger A.C., So, J.W., Cook, E.F., et al. (2004). An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. Journal of Evaluation in Clinical Practice, 10(4), 499-509.

National Kidney Foundation. (2002). K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Retrieved from

Ruggenenti, P., Perna, A., Remuzzi, G., & Gruppo Italiano di Studi Epidemiologici in Nefrologia. (2001). ACE inhibitors to prevent end-stage renal disease: When to start and why possibly never to stop: A post hoc analysis of the REIN trial results. Journal of the American Society of Nephrology, 12, 2832-2837.

Saseen J.J., & Carter, B.L. (2005). Hypertension. In J.T. DiPiro, R.I. Talbert, G.C. Yee, G.R. Matzke, B.G. Wells, & L.M. Posey. (Eds.), Pharmacotherapy: A pathophysiologic approach (pp. 185-217). The McGraw-Hill Companies, Inc.

Strippoli, G.F.M., Bonifati, C., Craig, M., Navaneethan, S.D., & Craig, J.C. (2006). Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD006257. DOI: 10.1002/14651858.CD006257.

by Lindsay Marie Creamer, BSc, Pharmacy Student, Memorial University of Newfoundland, St. John's, NL., and Jennifer Ryan, BSc Pharm, Pharm D, ACPR, Nephrology Pharmacist, Atlantic Health Sciences Corporation, Saint John, NB

Address correspondence to: Dr. Jennifer Ryan, BSc Pharm, Pharm D, ACPR, Nephrology Pharmacist, Atlantic Health Sciences Corporation, 400 University Avenue, Saint John, NB E5K 3Y2. E-mail:
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Article Details
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Title Annotation:Pharmacy news and reviews; angiotensin-converting enzyme; angiotensin receptor blockers
Author:Creamer, Lindsay Marie; Ryan, Jennifer
Publication:CANNT Journal
Article Type:Clinical report
Geographic Code:1CANA
Date:Oct 1, 2008
Previous Article:The Northern Alberta Renal Program dialysis bus.
Next Article:New CANNT board members 2008-2009.

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