INTRODUCTION — In addition to kidney function impairment, prolonged heavy analgesic use can lead to two other major complications: urinary tract malignancy and atherosclerotic disease. The development of these conditions in patients with chronic analgesic abuse and analgesic nephropathy is discussed here. The effects of nonsteroidal antiinflammatory drugs (NSAIDs) on cardiovascular risk and the association between analgesics and the risk for hypertension are presented separately:
●(See "NSAIDs: Adverse cardiovascular effects".)
●(See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)
URINARY TRACT MALIGNANCY — Transitional cell carcinomas of the kidney pelvis, ureter, and bladder (which may be multiple and bilateral) all occur with increased frequency in this setting [1-3]. The incidence of renal cell carcinoma also may be enhanced, but this remains controversial [4]. A large meta-analysis of 20 observational studies (14 with acetaminophen, 13 with aspirin, and 5 with other nonsteroidal antiinflammatory drugs [NSAIDs]) found that acetaminophen and nonaspirin NSAIDs were associated with a significantly increased risk of developing kidney cancer (relative risk 1.28, 95% CI 1.15-1.44 and 1.25, 95% CI 1.06-1.46, respectively) [5].
It is estimated that a urinary tract malignancy will develop in as many as 8 to 10 percent of patients with analgesic nephropathy [1-3] but in well under 1 percent of phenacetin-containing analgesic users without kidney disease [6]. In women under the age of 50 years, for example, analgesic abuse is the most common cause of bladder cancer, an otherwise unusual disorder in young women [3]. The potential magnitude of this problem has also been illustrated by histologic examination of nephrectomy specimens obtained prior to kidney transplantation; the incidence of urothelial atypia in this setting approaches 50 percent [1].
The tumors generally become apparent after 15 to 25 years of analgesic abuse [1], usually, but not always, in patients with clinically evident analgesic nephropathy [2]. There is no relationship between the degree of kidney failure in patients with analgesic nephropathy and the appearance of transitional cell carcinoma. Most patients are still taking the drug at the time of diagnosis, but clinically evident disease can first become apparent several years after cessation of analgesic intake and even after kidney transplantation has been performed [1]. In Australia, for example, the incidence of analgesic nephropathy declined progressively in the first 10 years after phenacetin-containing compounds were removed from over-the-counter analgesic combinations and five years after over-the-counter sales of analgesic mixtures were banned [7]. In comparison, the incidence of urinary tract malignancy continued to rise (at a greater rate than other malignancies), a possible reflection of late phenacetin-induced injury [7].
It is presumed that the induction of malignancy results from the intrarenal accumulation of N-hydroxylated phenacetin metabolites that have potent alkylating action [2]. Because of the urinary concentrating capacity of the kidney, the highest concentration of these metabolites will be in the renal medulla, ureters, and bladder, possibly explaining the predisposition to carcinogenesis at these sites.
The pathogenetic importance of phenacetin metabolites is suggested indirectly from the observation that there appears to be no association with transitional cell carcinomas of the urinary tract with the prolonged ingestion of other analgesics that can cause papillary necrosis but do not form these metabolites, such as acetaminophen and NSAIDs [8-11]. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)
The major presenting symptom of urinary tract malignancy in analgesic nephropathy is microscopic or gross hematuria. Thus, continued monitoring is essential, and new hematuria should be evaluated with urinary cytology and, if indicated, cystoscopy followed by computed tomography (CT) scan and/or magnetic resonance imaging (MRI) [12]. It may also be prudent to obtain yearly urine cytology for the first several years, if analgesics are discontinued, or indefinitely, if drug intake persists. (See "Etiology and evaluation of hematuria in adults".)
The incidence of urothelial carcinoma after kidney transplantation in patients with analgesic nephropathy is comparable with the general incidence of up to 10 percent of urothelial carcinomas in end-stage kidney disease patients with analgesic nephropathy. Removal of the native kidneys prior to kidney transplantation has also been suggested, but the efficacy of this regimen has not been proven [1]. (See "Clinical presentation, diagnosis, and staging of bladder cancer".)
ATHEROSCLEROSIS — Patients with analgesic nephropathy are more likely to develop premature aging and graying and atherosclerotic vascular disease (including myocardial infarction and thrombotic stroke) [6,13]. As examples, chronic ingestion of phenacetin-containing analgesic mixtures in women aged 30 to 49 years is, after 20 years, associated with a twofold increase in risk of myocardial infarction and a threefold increase in risk of all cardiovascular diseases [6]. It is possible that the analgesic microangiopathy that is the earliest sign of kidney injury [14] may play an important role in this problem; the incidence of other risk factors (such as hypercholesterolemia, smoking, and hypertension) does not appear to be enhanced when compared with patients with other forms of chronic kidney disease (CKD).
The effects of nonsteroidal antiinflammatory drugs (NSAIDs) on cardiovascular risk and the association between analgesics and risk for hypertension are presented separately. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)
SUMMARY
●Urinary tract malignancy – Transitional cell carcinomas of the kidney pelvis, ureter, and bladder (which may be multiple and bilateral) all occur with increased frequency in patients with heavy analgesic use and analgesic nephropathy. There is no relationship between the degree of kidney failure in patients with analgesic nephropathy and the appearance of transitional cell carcinoma. (See 'Urinary tract malignancy' above.)
●Atherosclerosis – Patients with analgesic nephropathy, as is the case in other forms of chronic kidney failure, are more likely than those in the general population to develop premature atherosclerotic cardiovascular disease (including myocardial infarction and thrombotic stroke). (See 'Atherosclerosis' above.)
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