Recommendation 3: The ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II-receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation)
This is the recommendation that I have most of a problem with. The most recent KDIGO guideline on the management of blood pressure in CKD is 85 pages long and although this degree of detail is not necessary for a guideline for general practioners, there is a substantial amount of nuance that has been missed and, in fact, I believe that this recommendation is potentially harmful.
It is clear from many RCTs going back to the 1980s that ACE/ARB therapy is indicated for the treatment of hypertension in all individuals with UACR>300mg/g. Similarly, ACE/ARB are also indicated for all diabetic patients who have a UACR>30mg/g. However, there is no clear evidence that ACE/ARB are preferred in non-diabetic patients with a UACR between 30 and 300 mg/g. The current KDIGO guidelines grade the evidence for the use of ACE/ARB in that setting as 2D (the lowest quality evidence) although there are suggestions from trials that there may be benefit.
However, for non-diabetic patients without albuminuria, there is no evidence that ACE/ARB reduce CVD or mortality relative to other antihypertensives. In fact, there is evidence that ACE/ARB are associated with more complications in non-proteinuric patients (AKI, hyperkalemia etc.) In the TRANSCEND trial the investigators studied the use of telmisartan in patients who could not tolerate ACE inhibitors. Of note, none of the patients had macroalbuminuria although all were high risk individuals. A pre-specified secondary analysis of this study examined renal outcomes and found no significant difference in the treatment group vs. placebo. However, when these patients were separated into those with and without albuminuria, there was a trend towards a benefit in those with albuminuria. In patients without albuminuria, there was an interaction for the main renal outcome (p=0.01) in the direction of harm (HR 2.35, CI 1.33-4.15). This result is not altogether surprising. In my (admittedly anecdotal) experience, the use of ACE/ARB in patients with non-proteinuric kidney disease is hazardous. These patients, usually elderly, are prone to hypotensive episodes and are exquisitely sensitive to volume depletion. the majority have vascular renal disease, even if they do not have clinically significant renal artery stenosis.
It appears that the authors of the recommendation did not take albuminuria into account when formulating this guideline. I would alter it to state that ACE/ARB should be first line therapy in patients with CKD and albuminuria but that they should be used with caution in patients with no albuminuria, particularly in the elderly and those with vascular renal disease. Score this a 0.
Recommendation 4: The ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoproteinn in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate quality evidence)
This is a pretty uncontroversial statement. Although the benefits of statins in patients with ESRD are no clear-cut, two recent meta-analyses have clearly demonstrated that statins reduce CV mortality in patients with early stage CKD. Score 1.
Overall, I would score these guidelines 2.5/4. Reading around this has certainly highlighted to me the lack of good RCTs to guide therapies that we treat as routine and suggests many avenues for future research although it is difficult at this stage to see who would pay for these studies as they would need to be extremely large and hence, very expensive.
This is the recommendation that I have most of a problem with. The most recent KDIGO guideline on the management of blood pressure in CKD is 85 pages long and although this degree of detail is not necessary for a guideline for general practioners, there is a substantial amount of nuance that has been missed and, in fact, I believe that this recommendation is potentially harmful.
It is clear from many RCTs going back to the 1980s that ACE/ARB therapy is indicated for the treatment of hypertension in all individuals with UACR>300mg/g. Similarly, ACE/ARB are also indicated for all diabetic patients who have a UACR>30mg/g. However, there is no clear evidence that ACE/ARB are preferred in non-diabetic patients with a UACR between 30 and 300 mg/g. The current KDIGO guidelines grade the evidence for the use of ACE/ARB in that setting as 2D (the lowest quality evidence) although there are suggestions from trials that there may be benefit.
However, for non-diabetic patients without albuminuria, there is no evidence that ACE/ARB reduce CVD or mortality relative to other antihypertensives. In fact, there is evidence that ACE/ARB are associated with more complications in non-proteinuric patients (AKI, hyperkalemia etc.) In the TRANSCEND trial the investigators studied the use of telmisartan in patients who could not tolerate ACE inhibitors. Of note, none of the patients had macroalbuminuria although all were high risk individuals. A pre-specified secondary analysis of this study examined renal outcomes and found no significant difference in the treatment group vs. placebo. However, when these patients were separated into those with and without albuminuria, there was a trend towards a benefit in those with albuminuria. In patients without albuminuria, there was an interaction for the main renal outcome (p=0.01) in the direction of harm (HR 2.35, CI 1.33-4.15). This result is not altogether surprising. In my (admittedly anecdotal) experience, the use of ACE/ARB in patients with non-proteinuric kidney disease is hazardous. These patients, usually elderly, are prone to hypotensive episodes and are exquisitely sensitive to volume depletion. the majority have vascular renal disease, even if they do not have clinically significant renal artery stenosis.
It appears that the authors of the recommendation did not take albuminuria into account when formulating this guideline. I would alter it to state that ACE/ARB should be first line therapy in patients with CKD and albuminuria but that they should be used with caution in patients with no albuminuria, particularly in the elderly and those with vascular renal disease. Score this a 0.
Recommendation 4: The ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoproteinn in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate quality evidence)
This is a pretty uncontroversial statement. Although the benefits of statins in patients with ESRD are no clear-cut, two recent meta-analyses have clearly demonstrated that statins reduce CV mortality in patients with early stage CKD. Score 1.
Overall, I would score these guidelines 2.5/4. Reading around this has certainly highlighted to me the lack of good RCTs to guide therapies that we treat as routine and suggests many avenues for future research although it is difficult at this stage to see who would pay for these studies as they would need to be extremely large and hence, very expensive.
3 comments:
I would push back on the acei/arb issue in only proteinuric CKD, looking at prospective randomized trials of medical therapy in patients with renal vascular disease is difficult, but the recent CORAL study provides a good look at what medical therapy (incl RAAS blockers) can accomplish in this pt. population. The benefit of looking at a study like this is that all patients had established renovascular disease by US and angiography of varying degrees, but aside from the lack of benefit with angioplasty/stenting, the control group was sick and had sig less mortality than expected, with minimal renal harm, similar BP reduction, all treated with RAAS blockers (among other agents), I forget the proteinuria breakdown but willing to bet most of these patients didn't have sig proteinuria.
Certainly the issue of the elderly, autonomically insufficient patients is a concern and therapy should be individualized, but I need more compelling data to keep me from rx'ing these drugs in patients with isolated vascular disease. I always think RAAS inhibitors should be rx'd for 3 reasons: dec cardiac remodeling, dec blood pressure, and dec proteinuria, I think the "renal" indications for these drugs should always be last as these patients die of cardiac deaths.
Thanks for your comment. I do believe that RAAS blockers are probably best for the majority of these patients. I just take issue with the fact that the recommendation unequivocally states that they should be first line therapy in patients with CKD and that this ignores potential problems in specific subgroups. As a nephrologist, I have been cionditioned to believe that ACEi are the best thing since sliced bread but they have to be used with caution which why I believe that this recommendation is flawed (and does not deal with the totality of the evidence)
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