Proteinurea : ACEi and ARB

• degree of proteinuria depends on the integrity (charge and size selectivity) of the glomerular capillary wall (GCW) and the intraglomerular pressure.
• Intraglomerular pressure is controlled by the afferent arteriole, which transmits systemic blood pressure to the glomerulus, and the efferent arteriole.
• Normalization of systemic blood pressure in a patient with hypertension should result in a reduction in intraglomerular pressure and a fall in albuminuria.

ACEi and ARB

• Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure by inhibiting angiotensin II ̶ mediated efferent arteriolar vasoconstriction
• These groups of drugs have a proteinuria-reducing effect independent of their antihypertensive effect
• Other hemodynamic and nonhemodynamic effects of ACE inhibitors may partly explain the renoprotective properties of this group of drugs, such as reduced breakdown of bradykinin (an efferent arteriolar vasodilator), restoration of size and charge selectivity to the GCW, and reduced production of cytokines that promote glomerulosclerosis and fibrosis, such as transforming growth factor (TGF)–beta

Choice of Agent

• no consistent differential effects of ACE inhibitors vs. ARBs on several potentially important clinical outcomes, including lipid levels, progression to type 2 diabetes mellitus, markers of carbohydrate metabolism/diabetes control, measures of left ventricular mass or function, and progression of renal disease, either based on creatinine, glomerular filtration rate or proteinuria.
• Target blood pressure is less than 125/75 mm Hg.
• dose of ACE inhibitor should be increased as tolerated until this blood pressure is achieved.
• Normotensive patients with proteinuria
• ACE inhibitors, because low doses usually are well tolerated and do not usually cause symptomatic hypotension.
• Patients who develop adverse effects from ACE inhibitors, such as cough/angioedema,
• An ARB may be used instead. Patients with mild hyperkalemia should receive dietary counseling.
• significant hyperkalemia
• should have the medication immediately discontinued and should be treated with a potassium-binding resin.
• ACE inhibitor or ARB does not adequately control proteinuria in a patient with chronic kidney disease (eg, diabetic nephropathy)
• a further reduction in proteinuria can be achieved by adding a mineralocorticoid receptor antagonist (MRA) such as eplerenone or spironolactone.
• However,  MRA is associated with a three- to eightfold increased risk for hyperkalemia

Combination: Disadvantage

• Avoid prescribing an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) for patients at high risk of vascular events or renal dysfunction.
• The combination does not reduce poor outcomes, and leads to more adverse drug-related events than an ACE inhibitor or ARB alone
• ONTARGET study demonstrated that combination therapy may cause further reduction in albuminuria but still adversely affect renal function.
• The combination study also casts fresh doubt on the assumption that proteinuria is an accurate surrogate marker for progressive renal dysfunction. The reduction in proteinuria seen in patients in the combination therapy group came at a cost of increased renal impairment.
• KDIGO guideline on CKD states there is insufficient evidence for use of combination of an ACEI and ARB to prevent the progression of CKD (not graded). 
• KDOQI guideline in patients with DM and CKD states that combination with an ACEI and ARB  cannot be recommended at this time, despite the potential benefit on further reduction in proteinuria   

Combination: Advantage

• There are limited data regarding the potential benefits of combined therapy with ACE inhibitors and ARBs.
• Several small studies have shown an additive antiproteinuric effect when both ACE inhibitors and ARBs are used in combination; however, this finding has not been replicated in all studies.
• In one recent, large study of nondiabetic kidney disease combination therapy was more effective than either agent alone in slowing the decline in GFR.

Recommendation

• Until additional information is available, the use of either one class or the other preferentially is recommended, rather than both classes together
• The majority of current evidence recommends against the combined use of ACE inhibitors and ARBs 

References:

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183919/
2. http://www2.kidney.org/professionals/kdoqi/guidelines_bp/guide_11.htm
3. ACE inhibitors and ARBs: cost-effectiveness and safety. S Afr Pharm J 2011;78(3):22–26
4. http://www.aafp.org/afp/2012/1015/p749.html 
5.  PBM-MAP-VPE Clinical Recommendations: Angiotensin II Receptor Antagonists