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Both angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs can lead to functional renal insufficiency. In an observational study we assessed the frequency of this adverse effect in patients aged over 75 years receiving these drugs in combination. In one year, out of 1500 patients whose records were screened, 12 were prescribed this combination. 2 developed acute renal failure, of whom one died and the other recovered after discontinuation of both drugs. 4 patients showed deterioration in renal function, which returned to normal after one of the drugs was stopped. Renal function remained stable in 6 patients: patients with deterioration in renal function were older and more likely to be on diuretics.
This drug combination is commonly nephrotoxic in the elderly and should be avoided, especially in those taking diuretics.
Angiotensin converting enzyme (ACE) inhibitors are increasingly used in the elderly for heart failure and hypertension. Another group of drugs commonly used in this age group are the nonsteroidal anti-inflammatories (NSAIDs). Since cardiac failure and hypertension often coincide with chronic pain in the elderly, co-prescription of these drugs is not infrequent. However, data on the renal safety of this combination in the elderly are very limited. A study of trandalopril and indometacin in hypertensive patients did not show any change in renal functional reserve, but the patients were young (mean age 53.5 years) and did not have any co-morbidity1. We undertook this study to assess the effects of combined therapy on renal function in the elderly.
A prospective observational study was conducted in a district general hospital over one year. Patients above 75 years of age from the care-of-the-elderly unit formed the study group. We reviewed all completed discharge prescriptions during this period. Patients with normal renal function on long-term treatment with either an ACE inhibitor or a NSAID (for at least three months), in whom the other drug was added during the present admission, were identified. During the study period, consultants in charge were unaware of the inquiry and so patients were prescribed this combination because of their perceived need, not to recruit them into the investigation. We noted baseline renal function at the start of combined therapy and again when the patients came for their routine outpatient review.
For both occasions we recorded use of other medications, especially diuretics; and if, on review, any drug had been stopped, the reason was identified from the case notes. In patients who showed renal deterioration, any associated illnesses and change in medication were noted. Acute renal failure (ARF) was defined as a sudden increase in serum creatinine from normal to more than 180 μmol/L2. Since there is no existing definition for renal deterioration, we arbitrarily defined it as an increase in serum creatinine of 50% above the baseline within six weeks (six weeks being chosen because it is the usual interval for an outpatient review after discharge). Even though this was an observational study, when patients failed to turn up for their review we requested the general practitioner to do the blood tests in the best interests of the patient.
During the one-year study period there were 2050 admissions to the unit. After exclusion of those with incomplete prescriptions, those transferred to community/rehabilitation hospitals (for which discharge prescriptions were usually unavailable), and those who died, information was collected on 1500 patients. Of these, 12 (6 males) had received an ACE inhibitor and a NSAID in combination. In 6 the ACE inhibitor had been prescribed first, in 6 the NSAID.
2 patients developed ARF, at six weeks and three months. Both were on diuretics and had had the NSAID added to ACE inhibitor. In the first patient, renal function did not improve after both drugs were stopped. Renal support was not considered because of coexisting metastatic liver disease and the patient died. The second patient had diarrhoea and hyponatraemia before the development of ARF. Both drugs were discontinued and renal function returned to normal after volume repletion.
4 patients showed deterioration in renal function between eight and twelve weeks. All were on diuretics and the dosage had not been altered since discharge. The NSAID was stopped in 3 and the ACE inhibitor in one, whereupon renal function returned to normal. In this group NSAID had been added to ACE inhibitor in one and ACE inhibitor to NSAID in 3. In the remaining 6 patients, renal function remained unaffected at six months: 2 were on diuretics; 3 had received the NSAID while on ACE inhibitor and 3 vice versa.
The group with deterioration in renal function had a higher mean age (83.3, range 78-88) than the group with stable renal function (78.6, range 75-82). Also, more of them used diuretics (6 versus 2). There was no obvious difference in baseline serum creatinine. None of the 6 patients with renal deterioration had paraproteinaemia; the relevant data are shown in Table 1.
As judged by this survey, co-prescription of an ACE inhibitor and a NSAID in the elderly commonly causes a deterioration in renal function. It could be argued that, in the 3 patients in whom an ACE inhibitor was added, unrecognized renovascular disease might have been responsible; but in 2 of these patients renal function returned to normal after stopping the NSAID (in the third patient the NSAID could not be stopped because of pain due to severe osteoarthritis). The temporal association between renal impairment with combination therapy and improvement after stopping one of the drugs indicates that the combined therapy was the cause of renal deterioration.
In a normal kidney, glomerular filtration is a function of glomerular blood flow, the balance of pressure across the capillary wall and the permeability and total surface area of the filtering capillaries. Adequate glomerular blood flow depends on cardiac output, prostaglandin-mediated afferent arteriolar vasodilatation and angiotensin II (A-II)-mediated efferent arteriolar vasoconstriction. The last two factors are especially important in states such as cardiac failure, hypovolaemia and renovascular disease, all of which are common in the elderly3. NSAID therapy inhibits cyclo-oxygenase, thus decreasing prostaglandin production; in consequence, afferent arteriolar flow lessens and glomerular filtration falls. ACE inhibitors depress A-II and thus inhibit A-II-mediated vasoconstriction. This lowers glomerular filtration pressure and decreases the glomerular filtration rate. A compensating reduction in systemic vascular resistance will normally raise the cardiac output and increase the renal blood flow, but elderly patients with limited myocardial reserve and volume depletion due to diuretics may not be able to increase their cardiac output sufficiently, with resultant renal hypoperfusion. The net effect of the combination therapy is a decrease in glomerular filtration rate, potentially aggravated by volume depletion and impaired myocardial function4.
NSAIDs and ACE inhibitors are the main causes of drug-induced ARF in the elderly5. Since sodium depletion is a precipitating factor, addition of a diuretic increases the risk of renal failure2. Published reports on the renal effect of this combination are sparse. The largest series is a retrospective study of 162 patients, of whom 3 developed ARF6; mean age and the presence or absence of other risk factors are not recorded. In another series of 27 patients with ARF due to an ACE inhibitor, 6 were also on a NSAID2. There are two case reports of nephrotoxicity in elderly patients due to this combination: a 72-year-old patient who also had undetected myeloma developed postoperative ARF17; and a patient aged 85 developed life-threatening hyperkalaemia8.
A limitation of our study is that the numbers are small. It is also possible that we missed some patients if the combination was prescribed during admission but was stopped before discharge because of renal deterioration. Co-prescription of these two drug groups was rare (0.8%) and we are unable to comment on individual NSAIDs or ACE inhibitors. We do, however, conclude that this combination poses a risk of renal failure in elderly patients receiving a diuretic, who are likely to have other age-related risk factors such as poor myocardial function, vascular disease and volume depletion.