Why Take This Patient Off Her ACEI?

Q: I sent a 68-year-old, hypertensive, diabetic woman with stage 4 kidney disease (estimated glomerular filtration rate [eGFR], 25 mL/min/1.73 m²; serum creatinine [SCr], 2 mg/mL) to a local nephrology group. Since she was diabetic, we had had her taking an angiotensin-converting enzyme inhibitor (ACEI) for years. The first thing the nephrology group did was take her off the ACEI. Why would they do that? I thought the hypertensive drug of choice for all diabetic patients is an ACEI or an angiotensin receptor blocker (ARB). Am I wrong?

A: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and intravascular volume through its effects on renin, angiotensin, and aldosterone production. Activation of RAAS causes an increase in blood pressure through vasoconstriction (angiotensin II effects) and the fluid retention associated with reabsorption of sodium and water (aldosterone effects). As such, the physiologic effects of RAAS have been implicated in the pathophysiology of cardiovascular diseases, such as heart failure, kidney disease, and hypertension.¹

The JNC 7 guidelines² (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommend the use of ACEIs or ARBs for the treatment of hypertension in patients with chronic kidney disease (CKD) or diabetes to slow progression of kidney disease. Given the benefits of ACEI or ARB therapy in reducing mortality in cardiovascular disease (for which patients with CKD are at increased risk³), these medications are indicated in patients with CKD.

Angiotensin II causes systemic vasoconstriction and also acts on the efferent arterioles of the glomerulus. ACEI/ARB therapy causes vasodilation of the efferent arterioles, thus lowering the intraglomerular capillary pressure.¹ This mechanism accounts for the antiproteinuric effect and the subsequent decrease in GFR when these agents are initiated.

Proteinuria is a marker that may indicate nephropathy and may lead to further kidney damage.¹ Slowing renal disease progression depends on controlling blood pressure and proteinuria.³

To date, a number of trials have been conducted to explore the benefit of the antiproteinuric effects of ACEI/ARB therapy. The antiproteinuric effect is more pronounced in patients with more severe proteinuria. Studies of these agents in patients with diabetic and nondiabetic nephropathy have shown that besides reducing proteinuria, they slow progression to end-stage renal disease (ESRD), thus delaying the need for renal replacement therapy.⁴ As such, ACEI/ARB therapy is widely used to reduce proteinuria, independent of the blood pressure–lowering effects.

Initiation of ACEI/ARB therapy is associated with an increase in SCr due to the drugs’ effects on the efferent arterioles, resulting in a decrease in intraglomerular pressure.³ However, discontinuing therapy is not warranted unless the SCr rises to more than 30% above baseline. According to findings from one meta-analysis, the degree of loss in renal function when ACEI therapy was initiated was inversely related to the rate of annual decline in renal function.⁵ Thus, patients with higher SCr levels at the start of therapy had poorer renal function initially, but they received the greatest benefit in long-term renal preservation.

The rise in SCr typically occurs within a few days of therapy initiation; thus, SCr should be measured within the first seven days of therapy.³ The SCr level is expected to stabilize within six to eight weeks of therapy. Patients whose SCr level continues to rise more than 30% to 35% above baseline may need to discontinue ACEI/ARB therapy; this rise may be attributed to kidney hypoperfusion. Kidney hypoperfusion can also occur when diuretics are initiated or their dosage increased, when NSAIDs are used, or in patients with bilateral renal artery stenosis or volume depletion resulting from gastroenteritis.³

Hyperkalemia due to decreased urinary excretion of potassium (K⁺) may present yet another reason to discontinue ACEI/ARB therapy in patients with CKD. Incidence of hyperkalemia in those with CKD stages 3 through 5 who receive either an ACEI or an ARB ranges from 5% to 50%.³ Hyperkalemia can occur when a long-acting ACEI is prescribed or when ACEI/ARB therapy is used concurrently with NSAIDs or potassium-sparing diuretics; thiazides or loop diuretics, by contrast, can reduce the risk for hyperkalemia.

Risk factors for moderate hyperkalemia (serum K⁺ ≥ 5.6 mmol/L) include age older than 65, congestive heart failure, SCr level greater than 1.6 mg/dL, and a blood urea nitrogen level exceeding 18 mg/dL.⁵

A dosing reduction or discontinuation of ACEI/ARB therapy should be considered when serum K⁺ levels are 5.6 mmol/L or greater.³ Patients who are older than 70 or whose serum urea nitrogen level exceeds 25 mg/dL are at increased risk for severe hyperkalemia (K⁺ > 6.0 mmol/L). Termination of an ACEI or an ARB may be warranted in patients with a serum K⁺ level exceeding 6.0 mmol/L or in those considered at increased risk for severe hyperkalemia.³

Other patients may also benefit from discontinuing ACEI/ARB therapy. Few data exist to support their use in patients with kidney function at 25% or less, or those with a GFR below 30 mL/min/1.73 m².³ Onuigbo⁶ suggests that ESRD in patients with CKD can either progress gradually and steadily or rapidly as a result of acute kidney injury (AKI). Patients with CKD who are at risk for ESRD because of AKI include those currently taking an ACEI or an ARB, older patients, and those who experience unexplained decreases in GFR.

To avoid any worsening of renal function, Onuigbo⁶ suggests temporarily discontinuing ACEI/ARB therapy in the following patients:

• 
Those older than 65 who are scheduled for colonoscopy, administration of IV radiocontrast, or surgery (especially cardiovascular surgery); or

• 
Patients hospitalized for an acute ailment.

Discontinuing these agents may prevent progression to ESRD in such patients.

In summary, use of ACEIs or ARBs to delay progression of renal disease may be continued if a clear therapeutic benefit exists. However, discontinuation should be considered if a patient with CKD is at risk for hyperkalemia or if the K⁺ level remains higher than 5.6 mmol/L, if SCr levels increase more than 30% above baseline, or if patients (especially those older than 65) are at risk for AKI.

References
1. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl. 2005;99:S57-S65.

2. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

3. Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24:168-175.

4. St Peter WL, Odum LE, Whaley-Connell AT. To RAS or not to RAS? The evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy. 2013 Apr 9.

5. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor–associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693.

6. Onuigbo MA. Is renoprotection with RAAS blockade a failed paradigm? Have we learnt any lessons so far? Int J Clin Pract. 2010;64:1341-1346.

Q: I sent a 68-year-old, hypertensive, diabetic woman with stage 4 kidney disease (estimated glomerular filtration rate [eGFR], 25 mL/min/1.73 m²; serum creatinine [SCr], 2 mg/mL) to a local nephrology group. Since she was diabetic, we had had her taking an angiotensin-converting enzyme inhibitor (ACEI) for years. The first thing the nephrology group did was take her off the ACEI. Why would they do that? I thought the hypertensive drug of choice for all diabetic patients is an ACEI or an angiotensin receptor blocker (ARB). Am I wrong?

A: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and intravascular volume through its effects on renin, angiotensin, and aldosterone production. Activation of RAAS causes an increase in blood pressure through vasoconstriction (angiotensin II effects) and the fluid retention associated with reabsorption of sodium and water (aldosterone effects). As such, the physiologic effects of RAAS have been implicated in the pathophysiology of cardiovascular diseases, such as heart failure, kidney disease, and hypertension.¹

The JNC 7 guidelines² (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommend the use of ACEIs or ARBs for the treatment of hypertension in patients with chronic kidney disease (CKD) or diabetes to slow progression of kidney disease. Given the benefits of ACEI or ARB therapy in reducing mortality in cardiovascular disease (for which patients with CKD are at increased risk³), these medications are indicated in patients with CKD.

Angiotensin II causes systemic vasoconstriction and also acts on the efferent arterioles of the glomerulus. ACEI/ARB therapy causes vasodilation of the efferent arterioles, thus lowering the intraglomerular capillary pressure.¹ This mechanism accounts for the antiproteinuric effect and the subsequent decrease in GFR when these agents are initiated.

Proteinuria is a marker that may indicate nephropathy and may lead to further kidney damage.¹ Slowing renal disease progression depends on controlling blood pressure and proteinuria.³

To date, a number of trials have been conducted to explore the benefit of the antiproteinuric effects of ACEI/ARB therapy. The antiproteinuric effect is more pronounced in patients with more severe proteinuria. Studies of these agents in patients with diabetic and nondiabetic nephropathy have shown that besides reducing proteinuria, they slow progression to end-stage renal disease (ESRD), thus delaying the need for renal replacement therapy.⁴ As such, ACEI/ARB therapy is widely used to reduce proteinuria, independent of the blood pressure–lowering effects.

Initiation of ACEI/ARB therapy is associated with an increase in SCr due to the drugs’ effects on the efferent arterioles, resulting in a decrease in intraglomerular pressure.³ However, discontinuing therapy is not warranted unless the SCr rises to more than 30% above baseline. According to findings from one meta-analysis, the degree of loss in renal function when ACEI therapy was initiated was inversely related to the rate of annual decline in renal function.⁵ Thus, patients with higher SCr levels at the start of therapy had poorer renal function initially, but they received the greatest benefit in long-term renal preservation.

The rise in SCr typically occurs within a few days of therapy initiation; thus, SCr should be measured within the first seven days of therapy.³ The SCr level is expected to stabilize within six to eight weeks of therapy. Patients whose SCr level continues to rise more than 30% to 35% above baseline may need to discontinue ACEI/ARB therapy; this rise may be attributed to kidney hypoperfusion. Kidney hypoperfusion can also occur when diuretics are initiated or their dosage increased, when NSAIDs are used, or in patients with bilateral renal artery stenosis or volume depletion resulting from gastroenteritis.³

Hyperkalemia due to decreased urinary excretion of potassium (K⁺) may present yet another reason to discontinue ACEI/ARB therapy in patients with CKD. Incidence of hyperkalemia in those with CKD stages 3 through 5 who receive either an ACEI or an ARB ranges from 5% to 50%.³ Hyperkalemia can occur when a long-acting ACEI is prescribed or when ACEI/ARB therapy is used concurrently with NSAIDs or potassium-sparing diuretics; thiazides or loop diuretics, by contrast, can reduce the risk for hyperkalemia.

Risk factors for moderate hyperkalemia (serum K⁺ ≥ 5.6 mmol/L) include age older than 65, congestive heart failure, SCr level greater than 1.6 mg/dL, and a blood urea nitrogen level exceeding 18 mg/dL.⁵

A dosing reduction or discontinuation of ACEI/ARB therapy should be considered when serum K⁺ levels are 5.6 mmol/L or greater.³ Patients who are older than 70 or whose serum urea nitrogen level exceeds 25 mg/dL are at increased risk for severe hyperkalemia (K⁺ > 6.0 mmol/L). Termination of an ACEI or an ARB may be warranted in patients with a serum K⁺ level exceeding 6.0 mmol/L or in those considered at increased risk for severe hyperkalemia.³

Other patients may also benefit from discontinuing ACEI/ARB therapy. Few data exist to support their use in patients with kidney function at 25% or less, or those with a GFR below 30 mL/min/1.73 m².³ Onuigbo⁶ suggests that ESRD in patients with CKD can either progress gradually and steadily or rapidly as a result of acute kidney injury (AKI). Patients with CKD who are at risk for ESRD because of AKI include those currently taking an ACEI or an ARB, older patients, and those who experience unexplained decreases in GFR.

To avoid any worsening of renal function, Onuigbo⁶ suggests temporarily discontinuing ACEI/ARB therapy in the following patients:

• 
Those older than 65 who are scheduled for colonoscopy, administration of IV radiocontrast, or surgery (especially cardiovascular surgery); or

• 
Patients hospitalized for an acute ailment.

Discontinuing these agents may prevent progression to ESRD in such patients.

In summary, use of ACEIs or ARBs to delay progression of renal disease may be continued if a clear therapeutic benefit exists. However, discontinuation should be considered if a patient with CKD is at risk for hyperkalemia or if the K⁺ level remains higher than 5.6 mmol/L, if SCr levels increase more than 30% above baseline, or if patients (especially those older than 65) are at risk for AKI.

References
1. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl. 2005;99:S57-S65.

2. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

3. Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24:168-175.

4. St Peter WL, Odum LE, Whaley-Connell AT. To RAS or not to RAS? The evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy. 2013 Apr 9.

5. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor–associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693.

6. Onuigbo MA. Is renoprotection with RAAS blockade a failed paradigm? Have we learnt any lessons so far? Int J Clin Pract. 2010;64:1341-1346.

Q: I sent a 68-year-old, hypertensive, diabetic woman with stage 4 kidney disease (estimated glomerular filtration rate [eGFR], 25 mL/min/1.73 m²; serum creatinine [SCr], 2 mg/mL) to a local nephrology group. Since she was diabetic, we had had her taking an angiotensin-converting enzyme inhibitor (ACEI) for years. The first thing the nephrology group did was take her off the ACEI. Why would they do that? I thought the hypertensive drug of choice for all diabetic patients is an ACEI or an angiotensin receptor blocker (ARB). Am I wrong?

A: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and intravascular volume through its effects on renin, angiotensin, and aldosterone production. Activation of RAAS causes an increase in blood pressure through vasoconstriction (angiotensin II effects) and the fluid retention associated with reabsorption of sodium and water (aldosterone effects). As such, the physiologic effects of RAAS have been implicated in the pathophysiology of cardiovascular diseases, such as heart failure, kidney disease, and hypertension.¹

The JNC 7 guidelines² (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommend the use of ACEIs or ARBs for the treatment of hypertension in patients with chronic kidney disease (CKD) or diabetes to slow progression of kidney disease. Given the benefits of ACEI or ARB therapy in reducing mortality in cardiovascular disease (for which patients with CKD are at increased risk³), these medications are indicated in patients with CKD.

Angiotensin II causes systemic vasoconstriction and also acts on the efferent arterioles of the glomerulus. ACEI/ARB therapy causes vasodilation of the efferent arterioles, thus lowering the intraglomerular capillary pressure.¹ This mechanism accounts for the antiproteinuric effect and the subsequent decrease in GFR when these agents are initiated.

Proteinuria is a marker that may indicate nephropathy and may lead to further kidney damage.¹ Slowing renal disease progression depends on controlling blood pressure and proteinuria.³

To date, a number of trials have been conducted to explore the benefit of the antiproteinuric effects of ACEI/ARB therapy. The antiproteinuric effect is more pronounced in patients with more severe proteinuria. Studies of these agents in patients with diabetic and nondiabetic nephropathy have shown that besides reducing proteinuria, they slow progression to end-stage renal disease (ESRD), thus delaying the need for renal replacement therapy.⁴ As such, ACEI/ARB therapy is widely used to reduce proteinuria, independent of the blood pressure–lowering effects.

Initiation of ACEI/ARB therapy is associated with an increase in SCr due to the drugs’ effects on the efferent arterioles, resulting in a decrease in intraglomerular pressure.³ However, discontinuing therapy is not warranted unless the SCr rises to more than 30% above baseline. According to findings from one meta-analysis, the degree of loss in renal function when ACEI therapy was initiated was inversely related to the rate of annual decline in renal function.⁵ Thus, patients with higher SCr levels at the start of therapy had poorer renal function initially, but they received the greatest benefit in long-term renal preservation.

The rise in SCr typically occurs within a few days of therapy initiation; thus, SCr should be measured within the first seven days of therapy.³ The SCr level is expected to stabilize within six to eight weeks of therapy. Patients whose SCr level continues to rise more than 30% to 35% above baseline may need to discontinue ACEI/ARB therapy; this rise may be attributed to kidney hypoperfusion. Kidney hypoperfusion can also occur when diuretics are initiated or their dosage increased, when NSAIDs are used, or in patients with bilateral renal artery stenosis or volume depletion resulting from gastroenteritis.³

Hyperkalemia due to decreased urinary excretion of potassium (K⁺) may present yet another reason to discontinue ACEI/ARB therapy in patients with CKD. Incidence of hyperkalemia in those with CKD stages 3 through 5 who receive either an ACEI or an ARB ranges from 5% to 50%.³ Hyperkalemia can occur when a long-acting ACEI is prescribed or when ACEI/ARB therapy is used concurrently with NSAIDs or potassium-sparing diuretics; thiazides or loop diuretics, by contrast, can reduce the risk for hyperkalemia.

Risk factors for moderate hyperkalemia (serum K⁺ ≥ 5.6 mmol/L) include age older than 65, congestive heart failure, SCr level greater than 1.6 mg/dL, and a blood urea nitrogen level exceeding 18 mg/dL.⁵

A dosing reduction or discontinuation of ACEI/ARB therapy should be considered when serum K⁺ levels are 5.6 mmol/L or greater.³ Patients who are older than 70 or whose serum urea nitrogen level exceeds 25 mg/dL are at increased risk for severe hyperkalemia (K⁺ > 6.0 mmol/L). Termination of an ACEI or an ARB may be warranted in patients with a serum K⁺ level exceeding 6.0 mmol/L or in those considered at increased risk for severe hyperkalemia.³

Other patients may also benefit from discontinuing ACEI/ARB therapy. Few data exist to support their use in patients with kidney function at 25% or less, or those with a GFR below 30 mL/min/1.73 m².³ Onuigbo⁶ suggests that ESRD in patients with CKD can either progress gradually and steadily or rapidly as a result of acute kidney injury (AKI). Patients with CKD who are at risk for ESRD because of AKI include those currently taking an ACEI or an ARB, older patients, and those who experience unexplained decreases in GFR.

To avoid any worsening of renal function, Onuigbo⁶ suggests temporarily discontinuing ACEI/ARB therapy in the following patients:

• 
Those older than 65 who are scheduled for colonoscopy, administration of IV radiocontrast, or surgery (especially cardiovascular surgery); or

• 
Patients hospitalized for an acute ailment.

Discontinuing these agents may prevent progression to ESRD in such patients.

In summary, use of ACEIs or ARBs to delay progression of renal disease may be continued if a clear therapeutic benefit exists. However, discontinuation should be considered if a patient with CKD is at risk for hyperkalemia or if the K⁺ level remains higher than 5.6 mmol/L, if SCr levels increase more than 30% above baseline, or if patients (especially those older than 65) are at risk for AKI.

References
1. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl. 2005;99:S57-S65.

2. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

3. Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24:168-175.

4. St Peter WL, Odum LE, Whaley-Connell AT. To RAS or not to RAS? The evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy. 2013 Apr 9.

5. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor–associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693.

6. Onuigbo MA. Is renoprotection with RAAS blockade a failed paradigm? Have we learnt any lessons so far? Int J Clin Pract. 2010;64:1341-1346.