ACE Inhibitors in CKD Flashcards
Effects of angiotensin II
At AT1 and AT2 G-protein coupled receptors:
- potent vasoconstrictor (esp efferent renal arterioles)
- Increased NA release –> vasoconstriction kidney and HR
- Increased kidney Na+ reabsorption
- Increased Adrenal cortex aldosterone secretion
- Increased Heart and artery cell growth
ACE
This is a membrane bound endothelial enzyme, which is abundant in the lungs but also present in other vascular tissues including the heart, brain, striated muscle,
What is ATII cleaved to form?
ATII cleaved by aminopeptidase A and N to produce ATIII and ATIV
» ATIII stimulates aldosterone secretion and involved in thirst
» ATIV increases the release of PAI-1 (plasminogen activator inhibitor-1)
Effects of aldosterone
Enhances Na+ reabsorption and K+ excretion in the principal cells of the collecting tubule.
Are ACE-Is and ARBs the same?
Other sources of angiotensin II may be important?
» Chymase also converts angiotensin I to angiotensin II
» Not inhibited by ACEIs
» ARBs may be more beneficial?
Some of the beneficial effects of ACEIs may be mediated by bradykinin/NO
» Bradykinin is a vasodilator via the endothelial NO pathway
» ACEIs may be more beneficial?
ACE-I’s vs ARBs in HTN
ARBs lower BP to a similar extent to ACEIs and
ß-blockers. ARBs more effective than ß-blockers in reducing mortality in patients with hypertension and left
ventricular hypertropy, especially in diabetes.
Reduce progression of diabetic nephropathy
ACEi vs ARBs and HF
Candesartan improves prognosis in HF, suitable
alternative to ACEI
ARBs may further decrease cardiovascular
morbidity when added to ACEI therapy in patients with systolic HF
May also increase risks of adverse effects
Candesartan vs losartan morbidity and mortality
ARBs are competitive antagonists of the AT1 receptor.
Candesartan was associated with lower mortality risk compared to Losartan.
Candesartan vs losartan cellular mechanisms
Candesartan: improves endothelial function, lowered plasma levels of plasminogen activator inhibitor 1 and monocyte chemoattractant protein 1
» 4 binding sites on the AT1 receptor
» Binds tightly, dissociation half life 120 mins
» “insurmountable antagonism”
Losartan, also improved endothelial function
» 2 binding sites on the AT1 receptor
» Binds loosley, dissociation half life of seconds-mins
Clinical uses of renin-angiotensin system inhibitors
- Hypertension (common cause of CKD)
- cardiac failure
- after MI (prophylactic)
- People at high risk of ischaemic heart disease
- Diabetic nephropathy » (common cause of CKD)
- Progressive renal insufficiency
CKD clinical definition
- Glomerular filtrationr ate(GFR) <60mL/min/ 1.73m2 that is present for ≥3 months with or without evidence of kidney damage; or
- Evidence of kidney damage with or without decreased GFR that is present for ≥3 months as evidenced by any of the following:
» microalbuminuria
» proteinuria
» glomerular haematuria
» pathological abnormalities
» (e.g. abnormal renal biopsy) » anatomical abnormalities
» (e.g. scarring seen on imaging or polycystic kidneys) »
Clinical Tip
» If the eGFR is ≥60 mL/min/1.73m2, and there is no evidence of kidney damage, then CKD is not present.
Key indicators of CKD
- Proteinuria: increased amounts of proteinuria correlated directly with an increased rate of progression to end-stage kidney disease. People at risk for CKD should be screened anually.
- Microalbuminuria: sensitive indicator of CKD in people with diabetes, indicates an increased risk of micro and macro vascular disease that requires aggressive intervention. Regular screening for diabetic patients is recommended.
Why is early detection of proteinuria and haematuria important?
Increasing amounts of protein in the urine correlate directly with an increased rate of progression into end-stage kidney disease. Reduction in the amount of proteinuria is associated with improved outcomes. Early intervention can reduce CKD progression and cardiovascular risk by 50% and improves quality of life
CKD management
- LIFESTYLE
Weight management, physical activity, limit alcohol intake to no more than 2 standard drinks per day (men), and one standard drink per day (women), cease smoking, low salt diet. - MULTIPLE MEDICATIONS (often 3 or more drugs)
- ACE inhibitor or ARB first line therapy. Overactive RAS is associated with diabetic nephropathy. The amount of proteinuria/albuminuria can be reduced significantly by the use of an ACE inhibitor or ARB agent singly or in combination.
- Diuretics should be used in most patients. Both thiazides and loop diuretics (e.g. frusemide) are effective as adjunct antihypertensive therapy. Additional agents can be chosen based on cardiovascular indications
- Beta-blockers may be useful in people with coronary heart disease, tachyarrhythmias and heart failure. They are contraindicated where there is asthma, chronic obstructive pulmonary disease and heart block.
- Calcium channel blockers may be used for people with angina, the elderly and those with systolic hypertension
Why are ACE inhibitors and ARBs used first line in CKD?
Angiotensin II-induced vasoconstriction increases glomerular hydraulic pressure, so much so that the size- selective function of the glomerulus is impaired
» allows filtration of proteins
Non-haemodynamic functions of angiotensin II
» Increased production of reactive oxygen species, up-regulation of cytokines, cell adhesion molecules and other inflammatory mediators.
Angiotensin II augments the renal production of aldosterone
» Principal mineralocorticoid
» Evidence now to suggest that it also directly contributes to endothelial dysfunction
» increases the size and stiffness of endothelial cells, which promotes protein leakage through gaps between the cells.
