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Should all patients with significant proteinuria take a renin-angiotensin inhibitor?
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George Thomas, MD
Joseph V. Nally, MD

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.1 Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.7 Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.8 Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.9,10

Trials discussed in this article

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.13

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.14 Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.15

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.21 If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

References
  1. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 2000; 57:1803–1817.
  2. Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45:281–287.
  3. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65:2309–2320.
  4. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349:1857–1863.
  5. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354:359–364.
  6. Agodoa LY, Appel L, Bakris GL, et al; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285:2719–2728.
  7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462.
  8. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994; 271:275–279.
  9. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134:370–379.
  10. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997; 349:1787–1792.
  11. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.
  12. Brenner BM, Copper ME, de Zeeuw D, et al; RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.
  13. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952–1961.
  14. Sharma P, Nagarajan V. Q: Can an ARB be given to patients who have had angioedema on an ACE inhibitor? Cleve Clin J Med 2013; 80:755–757.
  15. Kidney Disease Outcomes Quality Initiative (K/DOQI).K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43(suppl 1):S1–S290.
  16. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559.
  17. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547–553.
  18. Mann JF, Anderson C, Gao P, et al; ONTARGET Investigators. Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens 2013; 31:414–421.
  19. Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213.
  20. Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892–1903.
  21. American Diabetes Association. Microvascular complications and foot care. Sec. 9. In: Standards of Medical Care in Diabetes—2015. Diabetes Care 2015;38(suppl 1):S58–S66.
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Thomas_RAASInhibitorsForProteinuria.pdf
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George Thomas, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Joseph V. Nally, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Clinical Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: George Thomas, MD, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: thomasg3@ccf.org

Issue
Cleveland Clinic Journal of Medicine - 82(11)
Publications
Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Topics
Diabetes
Drug Therapy
Nephrology
Endocrinology
Page Number
716-718
Legacy Keywords
Proteinuria, nephropathy, renin-angiotensin system, angiotensin-converting enzyme inhibitors, ACE inhibitors, angiotensin II receptor blockers, ARBs, George Thomas, Joseph Nally
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Author(s)
George Thomas, MD
Joseph V. Nally, MD
Author(s)
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Joseph V. Nally, MD
Author and Disclosure Information

George Thomas, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Joseph V. Nally, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Clinical Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: George Thomas, MD, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: thomasg3@ccf.org

Author and Disclosure Information

George Thomas, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Joseph V. Nally, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Clinical Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: George Thomas, MD, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: thomasg3@ccf.org

Article PDF
Thomas_RAASInhibitorsForProteinuria.pdf
Article PDF
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Related Articles
Detecting and controlling diabetic nephropathy: What do we know?

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.1 Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.7 Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.8 Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.9,10

Trials discussed in this article

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.13

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.14 Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.15

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.21 If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.1 Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.7 Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.8 Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.9,10

Trials discussed in this article

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.13

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.14 Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.15

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.21 If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

References
  1. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 2000; 57:1803–1817.
  2. Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45:281–287.
  3. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65:2309–2320.
  4. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349:1857–1863.
  5. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354:359–364.
  6. Agodoa LY, Appel L, Bakris GL, et al; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285:2719–2728.
  7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462.
  8. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994; 271:275–279.
  9. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134:370–379.
  10. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997; 349:1787–1792.
  11. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.
  12. Brenner BM, Copper ME, de Zeeuw D, et al; RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.
  13. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952–1961.
  14. Sharma P, Nagarajan V. Q: Can an ARB be given to patients who have had angioedema on an ACE inhibitor? Cleve Clin J Med 2013; 80:755–757.
  15. Kidney Disease Outcomes Quality Initiative (K/DOQI).K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43(suppl 1):S1–S290.
  16. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559.
  17. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547–553.
  18. Mann JF, Anderson C, Gao P, et al; ONTARGET Investigators. Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens 2013; 31:414–421.
  19. Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213.
  20. Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892–1903.
  21. American Diabetes Association. Microvascular complications and foot care. Sec. 9. In: Standards of Medical Care in Diabetes—2015. Diabetes Care 2015;38(suppl 1):S58–S66.
References
  1. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 2000; 57:1803–1817.
  2. Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45:281–287.
  3. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65:2309–2320.
  4. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349:1857–1863.
  5. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354:359–364.
  6. Agodoa LY, Appel L, Bakris GL, et al; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285:2719–2728.
  7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462.
  8. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994; 271:275–279.
  9. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134:370–379.
  10. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997; 349:1787–1792.
  11. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.
  12. Brenner BM, Copper ME, de Zeeuw D, et al; RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.
  13. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952–1961.
  14. Sharma P, Nagarajan V. Q: Can an ARB be given to patients who have had angioedema on an ACE inhibitor? Cleve Clin J Med 2013; 80:755–757.
  15. Kidney Disease Outcomes Quality Initiative (K/DOQI).K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43(suppl 1):S1–S290.
  16. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559.
  17. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547–553.
  18. Mann JF, Anderson C, Gao P, et al; ONTARGET Investigators. Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens 2013; 31:414–421.
  19. Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213.
  20. Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892–1903.
  21. American Diabetes Association. Microvascular complications and foot care. Sec. 9. In: Standards of Medical Care in Diabetes—2015. Diabetes Care 2015;38(suppl 1):S58–S66.
Issue
Cleveland Clinic Journal of Medicine - 82(11)
Issue
Cleveland Clinic Journal of Medicine - 82(11)
Page Number
716-718
Page Number
716-718
Publications
Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Publications
Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Topics
Diabetes
Drug Therapy
Nephrology
Endocrinology
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Should all patients with significant proteinuria take a renin-angiotensin inhibitor?
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Should all patients with significant proteinuria take a renin-angiotensin inhibitor?
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Proteinuria, nephropathy, renin-angiotensin system, angiotensin-converting enzyme inhibitors, ACE inhibitors, angiotensin II receptor blockers, ARBs, George Thomas, Joseph Nally
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