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Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine
Director, Editorial Development, Medscape, LLC
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The prevalence of chronic kidney disease in the United States is increasing, and simple urine tests are effective tools to measure the risk for progression to chronic kidney disease. Angiotensin-converting enzyme inhibitors (ACEIs) have been demonstrated to reduce the risk for progression of proteinuria to more significant chronic kidney disease, but angiotensin receptor blockers (ARBs) may also be effective -- and possibly even more effective -- in this regard. The current review compares the effects of ACEIs and ARBs on proteinuria and also examines the clinical efficacy and safety of using ARBs and ACEIs concurrently for patients with proteinuria.
Kunz R, Friedrich C, Wolbers, 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
The study that this review is based on was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Out of a possible top score of 7, this study was ranked as 6 for relevance and 5 for newsworthiness by clinicians who used this system.
Chronic kidney disease (CKD) is common in the United States and appears to be growing in prevalence. In a comparison of data from the National Health and Nutrition and Examination Surveys from the periods 1988 through 1994 and 1999 through 2004, the prevalence of any CKD increased from 10.1% to 13.1% among noninstitutionalized adults.[1] The most significant increases in CKD occurred in stages 3 and 4 of the disease. Furthermore, a higher prevalence of hypertension and diabetes along with a higher than average body mass index fully explained the increase in the presence of albuminuria.
Most primary care clinicians gain experience with CKD in the setting of chronic disease management, particularly diabetes. Microalbuminuria is the earliest sign of diabetic nephropathy, and up to 40% of patients with this incipient sign of kidney disease have progression to overt nephropathy over the next 10 years.[2] Overall, end-stage renal disease eventually develops in 1 in 5 patients with diabetic nephropathy. It should also be noted that the mean interval between the diagnosis of diabetes and severe CKD is decreasing as type 2 diabetes becomes more prevalent. Kidney disease may develop in patients with relatively asymptomatic type 2 diabetes over many years before they begin receiving treatment improve the prognosis of kidney disease.
Even mild proteinuria as measured on a urine dipstick test can predict a higher risk for end-stage renal disease. In a study of 12,866 men followed for 25 years, the presence of dipstick proteinuria increased the hazard ratio of end-stage renal disease by a factor of 3.1 compared with men without proteinuria.[3] The combination of moderate proteinuria on urine dipstick and an estimated glomerular filtration rate less than 60 mL/minute increased the hazard ratio for end-stage renal disease by 41-fold.
Microalbuminuria can predict significant adverse events beyond end-stage renal disease. In fact, microalbuminuria has been independently associated with an increased risk for both cardiovascular disease and overall mortality.[4] Furthermore, the degree of albuminuria does not have to be clinically significant to increase these risks.
Given these potentially severe outcomes, patients and clinicians should do everything possible to reduce the clinical risks associated with nephropathy and chronic CKD. A recent study of patients with advanced renal insufficiency demonstrated that 20 mg/day of the ACEI benazepril reduced the composite risk of doubling of the serum creatinine level, end-stage renal disease, or death.[5] Benazepril was associated with a 52% reduction in the level of proteinuria and a 23% reduction in the rate of decline in renal function. The incidence of major adverse events in the benazepril and placebo treatment groups was similar.
In addition, a recent trial comparing the ARB telmisartan and the ACEI enalapril among patients with diabetic nephropathy and hypertension found that the 2 medications were associated with similar results in the combined endpoint of glomerular filtration rate, end-stage renal disease, and mortality.[6]
Such results beg the following questions: (1) should ARBs supplant ACEIs in the management of proteinuria, and (2) would the combination of an ACE inhibitor and an ARB provide the optimal protection for patients with proteinuria?
The current meta-analysis by Kunz and colleagues does an excellent job of answering these questions. Researchers examined MEDLINE and the Cochrane Library Central Register of Controlled Trials for relevant articles published between January 1990 and September 2006. They specifically searched for randomized controlled trials of at least 4 weeks' duration that evaluated treatment of patients with microalbuminuria or proteinuria. All studies included urinary protein excretion as an endpoint and compared ACE inhibitors, ARBs, or both with other medications or placebo.
The final pool of available trials included 49 trials involving a total of 6181 patients. The agents used in the studies are summarized below:
The authors were able to make 72 comparisons at 1 to 4 months of treatment and 38 comparisons at 5 to 12 months of treatment. In 24 of these comparisons, the cause of nephropathy was diabetes, and 19 comparisons were of strictly nondiabetic origin.
Most studies were small, with only 5 trials involving at least 100 subjects. Only 7 studies met all of the researchers' criteria for high quality, and nearly all of these trials compared ARBs with placebo. The authors of the current meta-analysis used a relative effect summary dubbed "ratio of means" to compare treatments in terms of their effects on proteinuria, with a lower ratio indicating improved efficacy in reducing proteinuria.
ARBs compared favorably with placebo in reducing proteinuria, with associated ratio of means values of 0.57 and 0.66 at the treatment time points of 1 to 4 months and 5 to 12 months, respectively. This effect was significant regardless of the cause or the degree of proteinuria. In comparing ARBs with calcium channel blockers, the respective ratios of means were again significant at 0.69 and 0.62. However, ARBs appeared similar to ACEIs in their ability to reduce proteinuria (ratios of means 0.99 at 1 to 4 months and 1.08 at 5 to 12 months).
Most significantly, the addition of ACEIs to ARBs reduced proteinuria to a greater degree than ARBs alone (ratio of means 0.76 at 1 to 4 months and 0.75 at 5 to 12 months). Combination therapy was also superior to treatment with ACEIs alone.
The 2 important conclusions that can be drawn from this meta-analysis are that ARBs are not superior to ACEIs in improving proteinuria, and that the combination of these 2 treatments appears superior in this outcome compared with either treatment alone. However, the authors of the meta-analysis lament that information regarding the tolerability and safety of combined therapy was insufficient. Overall, data regarding adverse events was lacking, and even if data were collected, patients recruited from these studies might not be representative of typical clinic patients with nephropathy. Compared with "real-world" patients, study patients tend to be younger and less likely to have comorbid conditions. In addition, they are more likely to be adherent to treatment.
In an attempt to address issues of safety, the meta-analysis pooled results regarding discontinuation of treatment. However, this effort was limited because the reasons for cessation of therapy were usually not provided in the original studies. Nonetheless, the rates of discontinuation for ARBs did not exceed those of ACE inhibitors and calcium channel blockers.
The researchers also reported the suggestion that combination therapy with an ARB and ACEI might lead to higher levels of treatment discontinuation. Rates of treatment discontinuation when comparing combination therapy with ARBs alone were 11.1% vs 0, respectively. Respective discontinuation rates of combination therapy vs ACEIs alone were 12.5% vs 0. However, the number of study participants included in these analyses was so small that no conclusions could be reached.
Two of the biggest safety concerns regarding the combination therapy include the risks for hyperkalemia and acute worsening of renal function. A review of the literature, however, suggests that these risks may not be significantly worse with combination treatment vs monotherapy. In one study of 24 patients with diabetic nephropathy, hyperkalemia developed in one subject receiving an ACEI alone and in another who received combination therapy with an ACEI and an ARB.[7] In another study of 108 adults with progressively chronic renal failure, ARB monotherapy was associated with a higher overall rate of adverse events compared with combination therapy.[8] One patient in the combination therapy group had to withdraw from the study because of hyperkalemia, but there were no study withdrawals because of an increase in serum creatinine.
One of the best reports regarding the safety of combination therapy with ARBs and ACEIs was delivered from the Candesartan and Lisinopril Microalbuminuria (CALM) study.[9] This trial examined combination therapy vs monotherapy among 199 patients with type 2 diabetes, hypertension, and microalbuminuria. Compared with monotherapy, combination treatment reduced blood pressure and the urinary albumin:creatinine ratio, and the most common adverse events were respiratory infection, cough, and headache, which occurred in less than 10% of all subjects. No significant sustained increases in levels of either serum potassium or creatinine occurred over 12 weeks, although creatinine clearance fell slightly compared with baseline values among subjects treated with lisinopril and combination therapy compared with participants who received candesartan alone. It should be noted that the CALM study excluded patients with moderate renal failure at baseline, and whether the combination therapy with an ACEI and ARB is safe for unselected and higher-risk patients with proteinuria in renal disease is an ongoing concern.
Beyond safety concerns, future research regarding combination therapy should attempt to focus on patient-centered outcomes, such as the use of renal replacement therapy, to validate the regular use of this regimen. However, such trials would have to involve many patients followed over a long period of time.
The current meta-analysis provides encouraging data for dual inhibition of the renin-angiotensin system among patients with proteinuria and renal disease. The combination of an ACEI and an ARB may be considered for individual patients, particularly for those who are not receiving significant benefit from monotherapy targeting proteinuria and who are at a low risk for possible adverse events.
