Introduction

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Angiotensin converting enzyme inhibitors are implicated in the pathogenesis of some cases of acute renal failure.¹ Renovascular disease is common, and an increased prevalence is associated with ageing and comorbid vascular disease. Unsuspected severe disease (>50% renal arterial stenosis) was found at postmortem in 42% of patients aged >75 years² and during angiographic studies in 15% investigated for coronary artery disease³ and 42% investigated for peripheral vascular disease.⁴ Renovascular disease has recently been found in 34% of elderly patients with cardiac failure.⁵ Angiotensin converting enzyme inhibitors are often indicated in all of these patient groups, and the risk of renal dysfunction is implicit in their association with renovascular disease.

Renal failure related to the use of angiotensin converting enzyme inhibitors, however, also occurs in the absence of severe renovascular disease. Vulnerable patients include those with hypovolaemia (for example, those receiving diuretics) or cardiac failure and elderly patients with intercurrent illness in whom compromised renal perfusion leads to dependence on the renin-angiotensin system for maintenance of glomerular filtration.⁶ These conditions may supervene only many months after the initiation phase of treatment. Although renal complications of treatment are acknowledged by the pharmaceutical companies, the need for caution is generally specified only in patients with renovascular disease; monitoring guidelines do not legislate for that larger population without renovascular disease which is also vulnerable to these agents.

We performed three separate studies. The pattern of use of angiotensin converting enzyme inhibitors and monitoring in the community was determined by a postal survey of general practitioners in one health region and by detailed analysis of prescribing data within one large inner city practice. In the final study we audited admissions to a regional renal unit for uraemia from the point of view of use of angiotensin converting enzyme inhibitors to examine the scale of the problem.

	Methods

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Postal questionnaire to general practitioners
In November 1996 we sent a questionnaire to 400 general practitioners working within the North Wales health authority. The questionnaire comprised four questions regarding their use of angiotensin converting enzyme inhibitors and monitoring of renal function. What were the clinical indications for treatment in their practice? Was renal function usually checked before the start of treatment? Was renal function monitored after the start of treatment? Would they welcome clearer guidelines on the monitoring of renal function in patients treated with angiotensin converting enzyme inhibitors? The postal questionnaires were returned anonymously, and the data were aggregated.

Audit of prescribing and monitoring
One general practice in central Manchester was selected for detailed audit as it had a large number of patients, was of acknowledged quality, and possessed a suitable patient database. The database was interrogated to identify all patients receiving angiotensin converting enzyme inhibitor currently (December 1996) or within the previous 12 months; the age distribution of the patient population; and all patients with a diagnosis of hypertension or cardiac failure.

Incidence of severe uraemia in patients presenting to a regional renal unit
A prospective audit of all new cases of severe uraemia (creatinine concentration >500 µmol/l or urea >35 mmol/l) presenting acutely to the renal department of Salford Royal Hospitals NHS Trust (catchment population for renal disease 1-1.25 million) was undertaken for the 12 months from June 1995. Patients with either acute or acute-on-chronic renal failure were included; aetiological factors for uraemia were determined; and cases in which angiotensin converting enzyme inhibitor treatment seemed important in the pathogenesis were evaluated in more detail. Thus clinical characteristics, patient and renal outcome, and details of monitoring by general practitioners were all documented.

Ethical considerations and statistical analysis
The study was reviewed by the local research ethics committee, which advised that a formal ethical application was not required.

	Results

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Postal questionnaire to general practitioners
Completed questionnaires were returned by 277 (69%) general practitioners. Their practice with respect to monitoring of renal function is shown in table 1. Only 93 (34%) checked renal function regularly after treatment with angiotensin converting enzyme inhibitors was started, and 42 (15%) admitted to never assessing it at any stage. Although 234 (84%) practitioners would welcome clear guidelines for monitoring of renal function when they prescribe these drugs to their patients, only one of the pharmaceutical companies provided such information.

Audit of prescribing and monitoring
Although the practice served a large student population, which swelled its numbers during term time, it also included 3625 city dwelling patients aged >35 years, and this typical subset of patients was used for audit. There were 390 (10.8%) patients with hypertension in this group and 117 (3.2%) with cardiac failure. Angiotensin converting enzyme inhibitors were prescribed to 162 (4.5%) patients (mean age 64.4 (SD 15.9) years, range 22-93 years), of whom 64 (40%) were aged 70 years or more. The 70 years group represented 36% of all patients with hypertension and 60% of the patients with heart failure in the practice.

Severe uraemia in association with angiotensin converting enzyme inhibitors
During the 12 month audit period 135 patients (mean age 62.1 (2.4) years; range 17-92 years) with severe uraemia were accepted by the unit. Causes of renal failure included prerenal uraemia or acute tubular necrosis (45), uraemic presentation of chronic renal failure (19), diabetic nephropathy (15), acute vasculitis or glomerulonephritis (14), renovascular disease (14), and urinary tract obstruction (12).

	Discussion

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These three divergent studies confirm that monitoring of renal function in patients treated with angiotensin converting enzyme inhibitors remains inadequate and cases of uraemia still commonly occur. This is of concern as current recommendations say that all patients with heart failure should be considered for treatment with angiotensin converting enzyme inhibitors⁷ and that major cost benefits may be derived by starting treatment in the community.⁸ There is no disputing the morbidity and survival advantages that such treatment conveys,⁹ but these recommendations must be accompanied by clear guidelines that encourage the detection of renal dysfunction and the most vulnerable patients at the earliest possible stage.

As the first study shows, such guidelines are usually not forthcoming from pharmaceutical companies, and most protocols within the medical literature make no provision for detecting late deterioration of renal function, ^{7 10} which seems to be the key area of patient management being overlooked. Although we accept that self reporting of clinical behaviour is often unreliable, it was surprising that only a third of the general practitioners who responded to the postal questionnaire admitted to monitoring renal function after initiation of angiotensin converting enzyme inhibitors, and nearly one in seven never checked function at any stage before or after treatment. It is unlikely that the practice of the 30% non-respondents would improve the results of this survey. Audit of the Manchester practice showed that even when there was an intention to monitor, renal function was actually assessed in few patients. Furthermore, although renal dysfunction was observed in 15 of 122 patients who received treatment initiated in general practice, most continued to receive treatment without further monitoring or investigation. Major concern derives from the 44 elderly patients (>70 years) in the practice who started treatment in the community, of whom 16 (36%) never had renal function monitored at any stage.

Extent of the problem
Some authors believe that the problem of renal dysfunction relating to use of angiotensin converting enzyme inhibitors is overstated¹¹; they refer to data from large trials in cardiac failure, usually those involving younger patients.⁹ We would argue that the risk of renal dysfunction increases significantly in elderly patients, a fact borne out by our current and previous¹ experiences and by the Elite study, in which 10.5% of elderly patients receiving captopril or losartan developed an increase of over 10% in serum creatinine concentration.¹² In our third study the nine (7%) patients whose uraemia could be attributable to treatment with angiotensin converting enzyme inhibitors were older than the other patients with uraemia. Most had been receiving treatment for many months and had no evidence of renovascular disease, but events which precipitated uraemia were usually identifiable. This elaborates an important point: although these drugs may be well tolerated by patients for many months or years, severe late renal dysfunction may complicate intercurrent illness (for example, influenza, pneumonia, gastroenteritis) when renal haemodynamic stress is increased by hypovolaemia and worsening cardiac function; these are the patients who require careful monitoring.

Possible guidelines
Our postal survey indicates that most general practitioners would welcome clear advice regarding monitoring of renal function in patients receiving angiotensin converting enzyme inhibitors (or angiotensin receptor blockers). We recommend that patients should be screened for risk factors predisposing them to uraemia (for example, old age, peripheral vascular disease, low cardiac output, or concomitant treatment with non-steroidal drugs or high dose diuretics). Renal function should be checked before and 7-10 days after treatment is started in all patients and thereafter regularly (for example, annually) only in those with risk factors. Most importantly, it should be assessed in all patients, especially the vulnerable, at times of relevant intercurrent illness (and if concomitant drug treatment is modified). Withdrawal from treatment should be considered if there are unexpected increases in serum creatinine concentration above the normal range or by 25% of the baseline value, or both. It is recognised, however, that the benefits of treatment to some patients outweigh this renal dysfunction (for example, those with severe cardiac failure) so that treatment should be continued, albeit with diligent monitoring. Patients with unexplained baseline renal dysfunction or with measurable dysfunction accompanying treatment should be considered for further renal investigation.

	Acknowledgments

Contributors: PAK had the original idea to amalgamate the three audits, performed the audit of acute renal failure, and wrote the manuscript. MK developed the questionnaire for general practitioners and performed the audit of general practitioner prescribing in North Wales. PMacD performed the audit of prescribing and monitoring angiotensin converting enzyme inhibitors in the Manchester practice. MOR contributed to the design of the study and reviewed the manuscript. PAK is guarantor for the study.

Funding: PMacD was supported by a local renal research grant from Salford Royal Hospitals NHS Trust.

Competing interests: None declared.

	References

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(Accepted 23 October 1998)