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. 1999 Jan 23;318(7178):257.

Taking precautions with angiotensin converting enzyme inhibitors

Angiotensin converting enzyme inhibitors are not proved to cause loss of renal mass

Jonathan D Louden 1, John Main 1
PMCID: PMC1114732  PMID: 9915742

Editor—We agree with Kumar et al that an awareness of the high risk of atherosclerotic renal artery stenosis is important in patients with vascular disease elsewhere, particularly if treatment with angiotensin converting enzyme inhibitors is being considered.1 We strongly disagree with the suggestion, however, that high risk patients starting treatment with angiotensin converting enzyme inhibitors should first be screened for unilateral renal artery stenosis, for two reasons.

Firstly, the assertion that angiotensin converting enzyme inhibitors cause loss of renal mass is unproved. Irreversible structural damage to kidneys with renal artery stenosis may result from hypertensive nephrosclerosis, cholesterol embolisation, ischaemia as a result of tight renal artery stenosis, and, ultimately, total occlusion.2 Angiotensin converting enzyme inhibitors cause an acute decrease in glomerular filtration rate, but in cases where this proves irreversible, the likeliest explanation is progression of the underlying disease. Renal blood flow is not specifically reduced by angiotensin converting enzyme inhibitors,3 although any drug that lowers blood pressure might reduce renal blood flow in the presence of clinically important renal artery stenosis.4 If screening for unilateral atherosclerotic renal artery stenosis were important, it would therefore be important for all high risk patients, not only those prescribed angiotensin converting enzyme inhibitors.

Secondly, however, we do not believe that screening for unilateral atherosclerotic renal artery stenosis is worth while. The rationale for screening would presumably be to prevent end stage renal failure secondary to bilateral renal artery occlusion. Evidence is lacking that percutaneous angioplasty, with or without stenting, prevents end stage renal failure in unilateral atherosclerotic renal artery stenosis.5

Although unilateral atherosclerotic renal artery stenosis is common and easy to find in high risk patients, current evidence does not tell us how to manage it once it is found.

References

  • 1.Kumar A, Asim M, Davison AM. Taking precautions with ACE inhibitors. BMJ. 1998;316:1921. doi: 10.1136/bmj.316.7149.1921. . (27 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Scoble JE, Cook JR. Individual kidney function in atherosclerotic nephropathy. Nephrol Dial Transplant. 1998;13:842–844. doi: 10.1093/ndt/13.4.842. [DOI] [PubMed] [Google Scholar]
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BMJ. 1999 Jan 23;318(7178):257.

Screening for unilateral renal artery stenosis cannot be justified

David R Murdoch 1

Editor—The editorial by Kumar et al reminds us that treatment with angiotensin converting enzyme inhibitors can cause harm in patients with unilateral or bilateral renal artery stenosis.1-1 Their suggestion, however, that patients at high risk should undergo screening with duplex ultrasonography is impracticable and would restrict its use in those for whom there is proved benefit.

Kumar et al’s definition of high risk includes most patients who are currently being treated with angiotensin converting enzyme inhibitors—elderly people with hypertension, and patients with diabetes or coronary heart disease. Implementing the recommendations of Kumar et al would have substantial clinical and financial implications. Duplex ultrasonography requires considerable technical skill, is not available in every centre, and is not currently thought to be sufficiently sensitive to be an effective screening method,1-2 even in patients with a technically adequate scan. Most patients with heart failure and almost all other patients have started treatment with angiotensin converting enzyme inhibitors in the community. What are the implications, therefore, for general practitioners without easy access to screening facilities?

Evidence from multiple randomised clinical trials shows that it is neither necessary nor possible to screen these patients. In the evaluation of losartan in the elderly study, treatment with either losartan or captopril was associated with only a 10.5% incidence of renal dysfunction, defined as a rise in serum creatinine of 26.5 μmol/l, despite patients’ advanced years (two thirds of patients aged over 70) and high incidence of diabetes (25%), hypertension (57%), and previous myocardial infarction (50%).1-3 Data from the fourth international study of infarct survival show that early oral treatment with angiotensin converting enzyme inhibitors after myocardial infarction was safe and associated with an additional 1.5 lives saved per 1000 patients treated within the first 24 hours.1-4 Screening this unstable population would be impossible. All these patients have coronary artery disease, and many have concomitant diabetes mellitus or peripheral vascular disease.

There is no evidence that angiotensin converting enzyme inhibitors are detrimental in unilateral renal artery stenosis. In a recent study of elderly patients with heart failure, many of whom had unilateral renal artery stenosis, angiotensin converting enzyme inhibitors were tolerated excellently.1-5 Furthermore, no evidence exists that relief of unilateral stenosis is associated with an improved outlook. What is, therefore, to be done with patients with unilateral stenosis? Are they to be denied the proved benefits of angiotensin converting enzyme inhibitors in the absence of evidence of harm? Kumar et al have not fully considered the implications of their recommendations. Currently, screening for unilateral renal artery stenosis cannot be justified.

References

  • 1-1.Kumar A, Asim M, Davison AM. Taking precautions with ACE inhibitors. BMJ. 1988;316:1921. doi: 10.1136/bmj.316.7149.1921. . (27 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Bude RO, Rubin JM. Detection of renal artery stenosis with Doppler sonography: it is more complicated than originally thought. Radiology. 1995;196:612–613. doi: 10.1148/radiology.196.3.7644618. [DOI] [PubMed] [Google Scholar]
  • 1-3.Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study—ELITE) Lancet. 1997;349:747–752. doi: 10.1016/s0140-6736(97)01187-2. [DOI] [PubMed] [Google Scholar]
  • 1-4.ISIS-4 Collaborative Group. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–685. [PubMed] [Google Scholar]
  • 1-5.MacDowall P, Kalra PA, O’Donoghue DJ, Waldek S, Mamtora H, Brown K. Risk of morbidity from renovascular disease in elderly patients with congestive cardiac failure. Lancet. 1998;352:13–16. doi: 10.1016/s0140-6736(97)11060-1. [DOI] [PubMed] [Google Scholar]
BMJ. 1999 Jan 23;318(7178):257.

Clinically significant deterioration in renal function occurs rarely

Tahseen A Chowdhury 1

Editor—Kumar et al urge caution in the increasingly widespread use of angiotensin converting enzyme inhibitors.2-1 This is a timely reminder that these drugs can cause problems in certain patients. They are now regarded as first line antihypertensive treatment in patients with diabetes, particularly if they have proteinuria.2-2 It is widely accepted that renal ultrasonography should be done in all patients with diabetes who have persistent proteinuria, in order to ensure that this has no non-diabetic cause. Asymmetrical renal size discovered this way can lead to the suspicion of unilateral renal artery stenosis. In addition, Doppler ultrasonography of the renal arteries, as suggested by Kumar et al, could also be done in these patients.

In view of the theoretical risk of clinically important unilateral renal artery disease, Kumar et al say that screening for renal artery stenosis is also required in all patients with diabetes, people aged over 50 with hypertension, and patients with coronary artery or peripheral vascular disease. This may not only lead to a considerable increase in cost for screening a large number of patients, but also provide a further reason to delay giving treatment that preserves cardiac and renal function to those most in need of it.

To ascertain whether angiotensin converting enzyme inhibitors have caused deterioration in renal function in patients at very high risk of renovascular disease, I have reviewed 20 patients with non-insulin dependent diabetes who have peripheral vascular disease (loss of dorsalis pedis and posterior tibial pulses in one or both feet, plus symptoms of claudication), who started treatment with angiotensin converting enzyme inhibitors at least 12 months previously for hypertension. None of these patients showed an acute deterioration in renal function. Evidence for this is a significant rise in serum creatinine (96 (SD 17) mmol/l before treatment, 93 (SD 23) mmol/l one year after treatment, P=0.672 (paired t test)). Furthermore, only one patient had clinically important asymmetry (>10%) in right and left renal function on radionuclide renography using diethylenetriaminepenta-acetic acid labelled with technicium-99m.

Although unilateral renal artery stenosis is common among the patient groups that Kumar et al recommend we screen, and a theoretical risk of acute deterioration in renal function exists, in practice a clinically important deterioration in renal function occurs rarely, even in a group of patients at very high risk of renal arterial disease.

References

  • 2-1.Kumar A, Asim M, Davison AM. Taking precautions with ACE inhibitors. BMJ. 1993;316:1921. doi: 10.1136/bmj.316.7149.1921. . (27 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456–1462. doi: 10.1056/NEJM199311113292004. [DOI] [PubMed] [Google Scholar]
BMJ. 1999 Jan 23;318(7178):257.

Funding for large scale screening is not available

Mark Ferris 1

Editor—Although we do not know whether treatment with angiotensin converting enzyme inhibitors hastens the loss of renal function in the long term when given to people with unsuspected unilateral renovascular disease, Kumar et al say that it might be wise to screen anyone at high risk with duplex or colour Doppler ultrasonography.3-1

The implications of this are far reaching. In my practice of 10 000 patients, 250 people over the age of 50 are prescribed angiotensin converting enzyme inhibitors. In this district, an estimated 2000 people would need screening each year and, assuming that 5% of these had clinically important renovascular disease, 100 would need a stent. The funding to do this on such a large scale does not exist, and I believe that we need more evidence than Kumar et al have provided either to divert the money from other, more proved uses or to restrict the use of angiotensin converting enzyme inhibitors. More information is needed before we alter clinical practice, which would probably mean using alternative drugs.

References

BMJ. 1999 Jan 23;318(7178):257.

Authors’ reply

A Kumar 1, M Asim 1, A M Davison 1

Editor—We wanted to increase awareness of the potential risks associated with the use of angiotensin converting enzyme inhibitors in patients with unsuspected atherosclerotic renal artery disease, prompted by the admission of several elderly patients with acute renal failure in whom renal function, as assessed by serum creatinine concentration, had not been checked before or after starting treatment with these drugs. Although such inhibition in the presence of bilateral renal artery stenosis is likely to be harmful, recent findings suggest that unilateral stenosis may be equally important.4-1 In some patients renal function in the kidney affected by stenosis is better than in the contralateral kidney with a normal artery.4-1 The kidney with the stenotic arterial lesion may thus be protected, at least in part, from the deleterious effects of hypertension and atheroembolic disease to which the other kidney is exposed. Injudicious use of an angiotensin converting enzyme inhibitor might lead to irreversible injury to the kidney that may be contributing most of a person’s glomerular filtration.

Louden and Main assert that any drug that lowers blood pressure might reduce renal blood flow in the presence of clinically important stenosis of the renal artery. Angiotensin converting enzyme inhibitors pose a greater hazard; in patients with hypertension due to unilateral atheromatous stenosis of the renal artery, the glomerular filtration rate in the stenotic kidney decreased markedly after inhibition of angiotensin converting enzyme, whereas it decreased only slightly with a calcium antagonist.4-2 Dependency on angiotensin II for the residual function in a kidney with stenosis of the artery, and a further decline in glomerular filtration after using these inhibitors, form the basis for angiotensin converting enzyme inhibitor renography as a diagnostic tool in unilateral arterial disease.4-3

Studies examining the efficacy and safety of angiotensin converting enzyme inhibitors and angiotensin II antagonists in treating heart failure in elderly people have shown that the prevalence of atherosclerotic renovascular disease in these patients is much greater than had been recognised previously.4-4,4-5 Murdoch suggests that a 10.5% incidence of renal dysfunction in patients taking these drugs in the evaluation of losartan in the elderly study4-4 is acceptable, but nephrologists find this approach alarming. How many of these patients would have developed progressive renal impairment had their renal function not been monitored as assiduously as happens during drug trials?

For elderly patients, particularly those with comorbid vascular diseases, the diagnosis of occult atherosclerotic renal artery stenosis is desirable, and careful monitoring of renal function essential in those for whom treatment with angiotensin converting enzyme inhibitors is being considered. The costs of screening for renal artery stenosis are far lower than the suffering and expense of kidney dialysis.

References

  • 4-1.Scoble JE, Cook GJR. Individual kidney function in atherosclerotic nephropathy. Nephrol Dial Transplant. 1998;13:842–844. doi: 10.1093/ndt/13.4.842. [DOI] [PubMed] [Google Scholar]
  • 4-2.Miyamori I, Yasuhara S, Matsubara T, Takasaki H, Takeda R. Comparative effects of captopril and nifedipine on split renal function in renovascular hypertension. Am J Hypertens. 1988;1:359–363. doi: 10.1093/ajh/1.4.359. [DOI] [PubMed] [Google Scholar]
  • 4-3.Taylor A, Nally J, Aurell M, Blaufox D, Dondi M, Dubovsky E, et al. Consensus report on ACE inhibitor renography for detecting renovascular hypertension. J Nucl Med. 1996;37:1876–1882. [PubMed] [Google Scholar]
  • 4-4.Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE) Lancet. 1997;349:747–752. doi: 10.1016/s0140-6736(97)01187-2. [DOI] [PubMed] [Google Scholar]
  • 4-5.MacDowall P, Kalra PA, O’Donoghue DJ, Waldek S, Mamtora H, Brown K. Risk of morbidity from renovascular disease in elderly patients with congestive cardiac failure. Lancet. 1998;352:13–16. doi: 10.1016/s0140-6736(97)11060-1. [DOI] [PubMed] [Google Scholar]

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