Captopril is approved by the FDA to treat diabetic nephropathy. Captopril decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (dialysis, need for renal transplantation, or death).11
Studies have shown the progression of kidney disease may be slowed by angiotensin-converting enzyme (ACE) inhibitors by reducing blood pressure, reducing proteinuria, improving renal blood flow, and improving interglomerular pressure due to the vasodilatory effects of ACE inhibitors.1-4
The 2017 ACC/AHA hypertension guidelines say that in adults with hypertension and chronic kidney disease (stage 3 or higher; or stage 1 or 2 with albuminuria [≥300 mg/d, or ≥300 mg/g albumin-to-creatinine ratio or the equivalent in the first morning void]), treatment with an ACE inhibitor is reasonable to slow kidney disease progression (Class of Recommendation [COR] IIa, Level of Evidence [LOE] B-R*).5
The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) recommends that an ACE inhibitor or ARB be used:
- In diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent) (2D**)
- In both diabetic and non-diabetic adults with CKD and urine albumin excretion >300 mg/24 hours (or equivalent) (1B**)
- In children with CKD in whom treatment with BP-lowering drugs is indicated, irrespective of the level of proteinuria (2D**) 6
A 2015 network meta-analysis of randomized trials examined the effect of antihypertensives on all-cause mortality and end-stage renal disease (ESRD) in adults with diabetic kidney disease. It found ACE inhibitor monotherapy significantly reduced progression to ESRD in people with diabetes compared to placebo (odds ratio [OR] 0.71, 95% confidence interval [CI] [0.51 – 1.01]). Combination therapy with an angiotensin receptor blocker (ARB) and an ACE inhibitor was superior (OR 0.62, 95% CI [0.43-0.90]), but this combination has some risk of increased hyperkalemia and acute kidney injury.7
A 1999 double-blind placebo-controlled trial of 186 patients with chronic non-diabetic nephropathy and persistent proteinuria found that progression to ESRD was significantly less in patients taking ramipril than placebo (9/99 vs 18/87, risk ratio [RR] 2.72, 95% CI [1.22 – 6.08]). Progression to overt proteinuria was also less in patients taking ramipril (15/99 vs 27/87, RR 2.40, 95% CI [1.27–4.52]).8
A 1996 random controlled trial of 583 patients with renal insufficiency from a variety of underlying diseases including glomerulopathies, interstitial nephritis, and diabetes found that benazepril slowed the progression of renal insufficiency except in patients with polycystic kidney disease. Overall unadjusted risk reduction of progressive renal insufficiency was 53% in the benazepril group (71% in those with mild insufficiency and 46% with moderate). The final changes in proteinuria from baseline in the 6-, 12-, 24-, and 36-month cohorts were -31, -40, -30, and -29% respectively for patients taking benazepril. For those taking a placebo, the final changes from baseline for each cohort were +15, +14, +14, and +9% respectively.9
Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system, such as ACE inhibitors. Patients whose renal function may depend on the activity of the renin-angiotensin system such as those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction, or volume depletion, may be at particular risk of developing acute renal failure on an ACE inhibitor. 1-14
*See ACC/AHA Class of Recommendation and Level of Evidence definitions below:
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Class (Strength) of Recommendation
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Class I (Strong)
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Benefit >>>> Risk
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Suggested phrases for writing recommendations:
· Is recommended
· Is indicated/useful/effective/beneficial
· Should be performed/administered/other
· Comparative-Effectiveness Phrases:
· Treatment/strategy A is recommended/indicated in preference to treatment B
· Treatment A should be chosen over treatment B
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Class IIa (Moderate)
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Benefit >> Risk
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Suggested phrases for writing recommendations:
· Is reasonable
· Can be useful/effective/beneficial
· Comparative-Effectiveness Phrases:
· Treatment/strategy A is probably recommended/indicated in preference to treatment B
· It is reasonable to choose treatment A over treatment B
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Class IIb (Weak)
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Benefit ≥ Risk
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Suggested phrases for writing recommendations:
· May/might be reasonable
· May/might be considered
· Usefulness/effectiveness is unknown/unclear/uncertain or not well established
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Class III: No Benefit (Moderate)
(Generally LOE A or B use only)
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Benefit = Risk
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Suggested phrases for writing recommendations:
· Is not recommended
· Is not indicated/useful/effective/beneficial
· Should not be performed/administered/other
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Class III: Harm (Strong)
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Risk > Benefit
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Suggested phrases for writing recommendations:
· Potentially harmful
· Causes harm
· Associated with excess morbidity/mortality
· Should not be performed/administered/other
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Level (Quality) of Evidence
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Level A
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· High-quality evidence from more than 1 randomized control trial (RCT)
· Meta-analyses of high quality RCTs
· One or more RCTs corroborated by high-quality registry studies
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Level B-R
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(Randomized)
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· Moderate-quality evidence from 1 or more RCTs
· Meta-analyses of moderate-quality RCTs
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Level B-NR
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(Nonrandomized)
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· Moderate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies
· Meta-analyses of such studies
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Level C-LD
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(Limited Data)
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· Randomized or nonrandomized observational or registry studies with limitations of design or execution
· Meta-analyses of such studies
· Physiological or mechanistic studies on human subjects
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Level C-EO
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(Expert Opinion)
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· Consensus of expert opinion based on clinical experience
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**See KDIGO grade for overall quality of evidence and description for grading recommendations below:
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Grade
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Quality of evidence
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Meaning
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A
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High
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We are confident that the true effect lies close to that of the estimate of the effect.
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B
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Moderate
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The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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C
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Low
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The true effect may be substantially different from the estimate of the effect.
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D
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Very low
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The estimate of effect is very uncertain, and often will be far form the truth.
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Implications
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Grade*
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Patients
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Clinicians
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Policy
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Level 1
“We recommend”
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Most people in your situation would want the recommended course of action and only a small proportion would not.
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Most patients should receive the recommended course of action.
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The recommendation can be evaluated as a candidate for developing a policy or performance measure.
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Level 2
“We suggest”
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The majority of people in your situation would want the recommended course of action, but many would not.
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Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.
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The recommendation is likely to require substantial de4bate and involvement of stakeholders before policy can be determined.
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*The additional category “Not Graded” was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.
References
- Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med 1995; 99 (5): 497-504.
- Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334 (15): 939-945.
- Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354 (9176): 359-364.
- Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385 (9982): 2047-2056.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension 2017.
- KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011) 2013; 3 (1): i-150.
- Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385 (9982): 2047-2056.
- Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354 (9176): 359-364.
- Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334 (15): 939-945.
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