Clinical manifestations and diagnosis of analgesic nephropathy

INTRODUCTION — Analgesic nephropathy is a kidney disease characterized by papillary necrosis and chronic interstitial nephritis and caused by the long-term consumption of nonnarcotic analgesic agents [1]. According to one definition, analgesic nephropathy results from the use of combination agents that contain two or more analgesic agents [2]. However, many believe that analgesic nephropathy may result from ingestion of any single analgesic agent that is taken long term [2]. The use of combination analgesics that contained phenacetin, which is no longer available, was particularly associated with analgesic nephropathy [3]. Phenacetin, however, was never used as a single analgesic.

The manifestations, diagnosis, differential diagnosis, and prognosis of analgesic nephropathy are reviewed here. The epidemiology, risk factors, and the associations with urinary tract malignancy and atherosclerotic cardiovascular disease are discussed separately. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on 'Chronic kidney disease associated with individual analgesic agents' and "Urinary tract malignancy and atherosclerotic disease in patients with chronic analgesic abuse".)

EPIDEMIOLOGY

●Prevalence – Analgesic nephropathy used to be one of the more common causes of chronic kidney disease (CKD), particularly in Australia and parts of Europe and the United States, but there was a marked decline in prevalence in the 1990s [4], which may have been related to the withdrawal of phenacetin from the market and to legislation that made certain combined analgesics available only by prescription [5-7]. The prevalence of analgesic nephropathy since the withdrawal of phenacetin is uncertain since a positive diagnosis is rarely made. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)

●Analgesic agent risk factors – In the post-phenacetin era, the amount and class of nonnarcotic analgesic agent that is associated with the development of analgesic nephropathy is unknown. Combination analgesic therapy (eg, aspirin plus acetaminophen) appears to confer an especially high risk, but the isolated use of large quantities of nonsteroidal antiinflammatory drugs (NSAIDs), whether nonselective or cyclooxygenase 2-specific, likely can induce CKD. Although observational data suggest that daily acetaminophen alone is associated with an increased risk of CKD, it is unlikely that acetaminophen use at recommended doses without the concomitant use of aspirin or other NSAIDs causes analgesic nephropathy. Similarly, the long-term administration of aspirin alone at recommended doses does not appear to induce kidney injury. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)

CLINICAL FEATURES

Clinical manifestations — Most patients who present with classic analgesic nephropathy are >45 years of age [8]. Usually, patients have no symptoms, and the disease is incidentally detected by laboratory studies that are performed for an unrelated problem and show an elevated creatinine or abnormal urinalysis.

Most patients have no symptoms referable to the urinary tract, although flank pain or hematuria from a sloughed or obstructing papilla may occur. Some patients (more commonly women) report a history of urinary tract infections [1]. In the studies cited above, a history of repeated urinary tract infection was present in up to 60 percent of patients [1,9-13].

Hypertension is commonly seen with moderate to advanced disease. In studies cited above, hypertension was present in up to 70 percent of patients [1,9-13].

Patients often have a history of chronic headaches or low back pain that leads to sustained, high-level nonnarcotic analgesic use. Other common problems include somatic complaints, such as malaise and weakness, and a history of peptic ulcer disease that may be related, in part, to aspirin and/or nonsteroidal antiinflammatory drug (NSAID) ingestion [1]. The frequency of reported history varies between studies [1]. In a review of studies from Europe and the United States, headache was present in 35 to 100 percent, and gastrointestinal symptoms were reported in 40 to 60 percent of patients [1,9-13].

Laboratory manifestations — The major laboratory manifestations include an elevated serum creatinine and a urinalysis showing hematuria or sterile pyuria. Patients usually have only mild proteinuria (<1.5 g/day) [1,14]. Although more prominent proteinuria (≥3.5 g/day) may occur among patients with advanced disease, this likely reflects secondary hemodynamically mediated glomerular injury. (See "Secondary factors and progression of chronic kidney disease".)

Anemia is commonly seen with moderate to advanced disease and may be disproportionate to the degree of kidney dysfunction. In the studies cited above, anemia was present in 60 to 90 percent of patients [1,9-13].

Radiographic manifestations — The following classic radiographic findings are detected by ultrasound and computed tomography (CT) scan [15,16]:

●Small kidneys

●Calcifications involving the renal papilla

●An indented or irregular contour

In a study of 60 patients with end-stage kidney disease (ESKD) without a known cause and a clear history of analgesic abuse, small kidneys, irregular kidney contours, and renal papillary calcification were detected in 100, 90, and 65 percent of patients, respectively [16]. CT scan is more sensitive than ultrasound for the detection of these findings. By contrast, irregular contours and papillary calcification are not commonly observed in patients with ESKD from most other causes. (See 'Diagnosis' below.)

Intravenous pyelography may show partial or total papillary necrosis, small kidneys, and blunted calyces similar to findings observed in chronic pyelonephritis.

DIAGNOSIS — A positive diagnosis of analgesic nephropathy is rarely made now that phenacetin is unavailable. This is because the radiographic findings that used to be considered diagnostic are rarely observed in the absence of phenacetin or combined analgesics containing addictive substances (eg, codeine). There are no diagnostic histologic changes that characterize analgesic nephropathy. The diagnosis is thus most often made as one of exclusion when the patient has a history of chronic nonnarcotic analgesic use and when other causes of an increased serum creatinine have been excluded by history, physical examination, urinalysis, and ultrasound.

Among patients who have a slowly rising serum creatinine, minimal proteinuria, and benign urinalysis (ie, no dysmorphic red blood cells or cellular casts), the diagnosis is suggested by a history of chronic nonnarcotic analgesic use typically related to chronic headaches, low back pain, or other somatic complaints. Because such patients may underreport the quantity of analgesics taken or may not report the ingestion of additional classes of analgesics, it is difficult to rule out a diagnosis of analgesic nephropathy based on a history of chronic medication use. However, we generally do not diagnose analgesic nephropathy in patients whose chronic analgesic exposure consists solely of isolated acetaminophen or aspirin use at recommended doses. (See 'Epidemiology' above.)

We generally obtain an ultrasound as the initial imaging test among all patients who present with an elevated creatinine from any cause. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Radiologic studies'.)

The ultrasound may suggest the diagnosis of analgesic nephropathy, although a computed tomography (CT) scan without contrast is more likely to reveal the diagnosis and is considered the diagnostic test of choice. (See 'Radiographic manifestations' above.)

However, the studies that defined the classic radiographic features of analgesic nephropathy were performed in populations where phenacetin-associated analgesic nephropathy was fairly common.

Diagnostic criteria for analgesic nephropathy on CT scan are bilateral reduced kidney size, "bumpy" or irregular renal contours, and bilateral papillary calcifications (ie, small, indented, calcified kidneys) (figure 1) [15,17,18]. These findings are typically lacking or less prominent with chronic interstitial nephropathies that are not associated with the use of combined analgesics [17,19]. (See 'Differential diagnosis' below.)

The sensitivity and specificity of these radiographic criteria for the diagnosis of analgesic nephropathy have been examined in a number of studies [15,18,20]. Since there is no "gold standard" for diagnosing analgesic nephropathy, these studies have compared radiographic findings with questionnaire-derived information about the frequency of use of analgesics prior to being diagnosed with kidney disease. As noted above, the ability to predict heavy analgesic use has differed in various studies, depending upon the year and country in which the study was performed [4,15,18,21]. This most certainly reflects differences in analgesic use over time and among different countries.

The variability is illustrated by the following two studies of patients with advanced kidney disease without a clearly identified etiology:

●In a multicenter study that was performed in Europe during the early 1990s, questionnaires were administered to ascertain past analgesic use, and CT scans without contrast were performed among patients with kidney disease of no known cause [15]. Although phenacetin-containing analgesic agents had been banned for a number of years before this study was performed, many patients presenting with chronic interstitial nephritis at the time of enrollment had taken large amounts of phenacetin-containing and non-phenacetin-containing analgesic mixtures during the 20 years prior to presentation. Papillary calcifications detected by CT scan had a sensitivity of 92 percent and a specificity of 100 percent for predicting heavy analgesic use.

In another study performed in 1992 in the former Czechoslovakia, of 149 patients who were initiating dialysis and had no clear kidney diagnosis, analgesic nephropathy was diagnosed using CT imaging criteria among 30 patients [20]. Of these, 24 acknowledged heavy analgesic use in interviews, and two additional patients were suspected by clinicians of analgesic abuse. In only four patients was a history of analgesic use not elicited.

Other reports that suggested that CT scans were useful for the diagnosis of analgesic nephropathy were also in populations of relatively high prevalence [22,23]. In such populations, and in the appropriate clinical setting, CT scanning without contrast can assist in the diagnosis of analgesic nephropathy at any degree of kidney function impairment, even among patients without a reliable history of analgesic abuse [4,15,21]. CT scan is more sensitive than ultrasound detection of characteristic morphologic features of analgesic nephropathy. In the study cited above, among patients with a history of heavy analgesic use, CT scan had a much higher sensitivity as compared with ultrasound for the detection of papillary calcification (87 versus 40, percent, respectively) and irregular contours (50 versus 30 percent, respectively) [15].

●However, in a later study from the United States, the sensitivity of CT scan ranged from 5 to 26 percent, depending upon how heavy analgesic use was defined [18]. One possible explanation for the much lower sensitivity than in the European study is that use of combined analgesic preparations with phenacetin was uncommon in the United States in the years preceding the study. As a result, the prevalence of analgesic nephropathy was too low to determine with any accuracy the sensitivity of CT for diagnosis.

Thus, classic CT findings as defined above are specific and sensitive for the diagnosis of analgesic nephropathy in areas and time periods when use of combination analgesics containing phenacetin was prevalent. However, CT does not appear to have high sensitivity for the diagnosis of analgesic nephropathy in populations and in time periods in which these drugs are not used.

Many clinicians do not obtain a CT among patients who have a history and urinalysis consistent with analgesic nephropathy, since a positive diagnosis rarely changes the management. This is because there is no specific treatment for analgesic nephropathy, except avoidance of analgesics such as acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs), and virtually all clinicians recommend the avoidance of analgesic agents among patients with chronic kidney disease (CKD) from any cause. However, there are occasions when the documentation of classic radiographic findings (such as papillary calcification and irregular contours) may allow one to avoid a more invasive test such as a kidney biopsy.

We generally do not perform a biopsy among patients who have classic CT manifestations of analgesic nephropathy and a history of analgesic overuse, since the radiographic manifestations are sufficient for diagnosis among patients with this history. However, among patients who do not have classic radiographic features, we occasionally perform a biopsy in order to exclude other conditions that also present with a slowly rising creatinine. (See 'Patients who do not have classic radiographic features' below.)

Among such patients, a biopsy does not provide a positive diagnosis of analgesic nephropathy, because histology generally shows only nonspecific tubulointerstitial fibrosis, but may identify other conditions. (See 'Patients who do not have classic radiographic features' below.)

Other radiographic tests, including intravenous pyelography and Doppler ultrasound, are no longer used for the diagnosis of analgesic nephropathy.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of analgesic nephropathy is different depending upon whether or not classic radiographic findings are observed.

Patients with classic radiographic findings — Among patients with classic radiographic findings, the differential diagnosis includes all causes of papillary necrosis such as sickle cell disease, chronic pyelonephritis, diabetes, and renal tuberculosis.

Sickle cell disease, chronic pyelonephritis, and diabetes are generally distinguished by history. Tuberculosis may be more difficult to exclude. Renal tuberculosis, rather than analgesic nephropathy, is suggested by certain radiographic findings, including unilateral disease, and extrarenal findings, including a contracted bladder and calcifications of the vas deferens, seminal vesicles, or prostate. Ultimately, renal tuberculosis is excluded by appropriately obtained urine cultures. (See "Urogenital tuberculosis".)

Patients with autosomal dominant polycystic kidney disease may occasionally present with papillary necrosis, but other characteristic radiographic findings (cysts) allow this to be easily excluded.

Medullary sponge kidney is associated with medullary calcification, but not with irregular kidney contour that is characteristic of analgesic nephropathy, and, thus, can be easily distinguished radiographically.

Patients who do not have classic radiographic features — Among patients who do not have characteristic radiographic features, the differential diagnosis includes nephrosclerosis and other forms of chronic interstitial nephritis such as sarcoidosis and infection-related acute interstitial nephritis (including tuberculosis), aristolochic acid containing herb nephropathy, myeloma kidney, medullary cystic kidney disease, medullary sponge kidney, and hypercalcemia. All are easily differentiated by the clinical context or simple laboratory determinations. (See appropriate topic reviews.)

PROGNOSIS — The course of the kidney disease depends both upon the severity of the kidney damage at the time of presentation and upon whether combined analgesic drug therapy is discontinued [1,19,24,25].

The decline in kidney function can be expected to progress if analgesics are continued. As an example, in one study of 78 patients with analgesic nephropathy, there was a sixfold increased risk of reaching the combined endpoint of death or dialysis in patients who continued to use analgesics [19]. Even aspirin, which is generally not nephrotoxic when given alone [26], can promote further kidney damage in analgesic nephropathy [24,25].

By contrast, kidney function stabilizes or mildly improves in most patients with mild reduction in estimated glomerular filtration rate (GFR; ie, 30 to 89 mL/min/1.73 m²) and if analgesic consumption is discontinued [24,25]. If, however, the kidney disease is already advanced, then progression may occur in the absence of drug intake, presumably due to secondary hemodynamic and metabolic changes associated with nephron loss [19,27]. (See "Secondary factors and progression of chronic kidney disease".)

The late course of analgesic nephropathy also may be complicated by two additional problems related to chronic analgesic use: malignancy and atherosclerotic disease. Patients with known analgesic nephropathy should be monitored for the development of hematuria. New hematuria should be investigated. (See "Urinary tract malignancy and atherosclerotic disease in patients with chronic analgesic abuse" and "Etiology and evaluation of hematuria in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY

●Overview – Analgesic nephropathy is characterized by papillary necrosis and chronic interstitial nephritis and caused by the long-term consumption of nonnarcotic analgesic agents. Analgesic nephropathy used to be one of the more common causes of chronic kidney disease (CKD), but the reduced availability of phenacetin and combination analgesics has led to a marked reduction in the number of new cases. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features – Most patients with analgesic nephropathy are women >45 years of age with a history of chronic pain that leads to the analgesic use. These patients may also have other somatic complaints (such as malaise and weakness) and ulcer-like symptoms that may be related to nonsteroidal antiinflammatory drug (NSAID) ingestion. Analgesic nephropathy is characterized by slowly progressive CKD, a urinalysis that may be normal or reveal sterile pyuria, and varying degrees of usually mild proteinuria. Hypertension and anemia are commonly seen with moderate to advanced disease. (See 'Clinical features' above.)

●Diagnosis – Computed tomography (CT) scan without contrast may assist in the diagnosis of analgesic nephropathy at any degree of kidney function impairment, even among those without a reliable history of analgesic abuse. Diagnostic criteria for analgesic nephropathy on CT scan are bilateral reduced kidney size, "bumpy" renal contours, and papillary calcifications (ie, small, indented, calcified kidneys) (figure 1). (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of this clinical presentation includes urinary tract obstruction, polycystic kidney disease, nephrosclerosis, and other causes of chronic tubulointerstitial disease, such as multiple myeloma, hypercalcemic or sarcoid nephropathy, medullary cystic kidney disease, medullary sponge kidney, and aristolochic acid containing herbs nephropathy, all easily differentiated by the clinical context or simple laboratory determinations. (See 'Differential diagnosis' above.)

●Prognosis – The decline in kidney function can be expected to progress if analgesics are continued. On the other hand, kidney function stabilizes or mildly improves in many patients with mild reduction in estimated glomerular filtration rate (GFR; ie, 30 to 89 mL/min/1.73 m²) and if analgesic consumption is discontinued. (See 'Prognosis' above.)