Chronic Analgesic Nephropathy Research Articles

Over-the-Counter Analgesic Use

Chronic analgesic nephropathy, particularly chronic interstitial nephritis and renal papillary necrosis, results from daily use for many years of mixtures containing at least two analgesics and caffeine or dependence-inducing drugs. Computed tomography scan can accurately diagnose this disease even in the absence of reliable information on previous analgesic use. The occasion to moderate regular use of aspirin and nonsteroidal anti-inflammatory drugs is without renal risk when renal function is normal. Paracetamol use is less clear although the risk is not great. The continued use of non-phenacetin-combined analgesics with or without nonsteroidal anti-inflammatory drugs is associated with faster progression toward renal impairment. As long as high-risk analgesic mixtures are available over the counter, analgesic nephropathy will continue to be a problem.

Blutungskomplikation durch Akkumulation von niedermolekularem Heparin bei einer Patientin mit Niereninsuffizienz

We report of a 71-year-old woman with a history of chronic analgesic nephropathy, who underwent coronary angiography. Because of anterior ventricular aneurysm, anticoagulation with nadroparine was installed. Continued ACE-inhibitor and ASA with additional intravenous contrast substance lead to acute tubular necrosis with rapid decline of the renal function. Due to accumulation of the low molecular weight heparin, the patient developed an extensive retroperitoneal haematoma with circulatory shock and temporary anuric kidney failure. Low molecular weight heparins are commonly used during percutaneous coronary interventions. They are as safe and efficient compared to unfractioned heparin. But due to their renal elimination, they have to be monitored by measuring anti-factor Xa-activity if creatinine-clearance is <30 ml/min.

Nonnarcotic analgesics: prevalence and estimated economic impact of toxicities.

To review and compare the risks of nonnarcotic analgesic toxicities in adults and estimate the relative healthcare costs of these toxicities, since direct comparison of costs is not possible. A MEDLINE search of the literature from 1969 to 1995 was used to identify pertinent data. Additional references were identified from articles obtained in the search. Information was obtained from prospective, retrospective, controlled, and uncontrolled studies; case reports; and review articles. Estimates of annual US costs of toxicities were extrapolated and synthesized from data from diagnosis-related groups, published information about the incidence of toxicity, or local data. Chronic use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a high incidence of acute renal toxicity and gastrointestinal toxicity. The most common problems associated with acetaminophen use are hepatoxicity after acute problems ingestion of large doses (> 10 g) or habitual use of smaller doses (< 4 g), particularly in alcoholic patients, and chronic analgesic nephropathy. Aspirin use is associated with a high incidence of gastrointestinal and acute renal toxicity in certain patient groups. Available data suggest that acetaminophen, used intermittently, remains the nonnarcotic analgesic of choice in many patient populations, including those with impaired renal function, gastrointestinal disease, and bleeding disorders. Estimated annual US costs associated with the toxicities of acetaminophen (excluding hepatotoxicity), aspirin (acute upper gastrointestinal bleeding only), and NSAIDs (excluding non-upper gastrointestinal hemorrhagic complications and hepatotoxicity) are about $51.5 million, $358.6 million, and $1.35 billion, respectively. Intermittent use of most nonnarcotic analgesics produces a small risk of chronic renal or hepatic toxicity. Gastrointestinal toxicity, especially upper gastrointestinal bleeding, remains a significant problem with NSAIDs and aspirin. Acetaminophen remains the nonnarcotic analgesic of choice for intermittent use by most patient groups. The toxicities associated with NSAIDs constitute about 72.6% of the total toxicities (costs $1.86 billion) caused by NSAIDs, acetaminophen, and aspirin.

Acetaminophen: Acute and chronic effects on renal function

Acetaminophen (APAP) is normally metabolized in the liver and kidney by P450 enzymes. No toxicity is observed with therapeutic doses of APAP. However, after ingestion of large quantities of APAP (>2,000 mg/kg), highly reactive quinones, metabolites of APAP, are generated; these react with glutathione and sulfhydryl groups on critical proteins, resulting in cellular dysfunction and hepatic and renal toxicity. The P450 metabolizing enzymes differ somewhat in character between the liver and kidney. Factors that enhance renal toxicity include chronic liver disease, possibly gender, concurrent renal insults, and conditions that alter the activity of P450-metabolizing enzyme systems. Acute renal toxicity is characterized by cellular injury primarily confined to the proximal tubule and significant reductions in glomerular filtration rate. However, there is little evidence that chronic administration of APAP contributes to chronic renal disease and analgesic nephropathy. The only report on this subject suggests that combination therapy with aspirin is required for medullary damage in rats. No evidence exists for the development of chronic analgesic nephropathy with APAP alone. Epidemiologic studies in healthy individuals have failed to demonstrate a significant correlation between APAP use and chronic renal disease and classic analgesic nephropathy. Therefore, large doses of APAP can produce both renal and hepatic failure, but little evidence exists for production of classic analgesic nephropathy with the use of APAP alone.

Acetaminophen/aspirin mixtures: Experimental data

The pertinent literature concerning the experimental induction of analgesic nephropathy is reviewed. Based on the accumulated data from animal experiments that induced a pathologic lesion resembling chronic analgesic nephropathy, of the limited number of analgesics tested, aspirin seems to be the most nephrotoxic of the commonly available analgesics. When aspirin is combined with other analgesics, the limited data available suggest at least an additive nephrotoxic effect, if not a synergism. The histologic presentation of acute intoxication is substantially different from that following chronic ingestion. With improvements in pathologic analysis of experimental results, future studies may well provide more insight as to the significance, relative contribution, and risk of combination analgesic products in inducing experimental analgesic nephrotoxicity.

Tell Your Kidneys to Take a Powder

To the Editor.— — Stillman and Schlesinger 1 recently elegantly reviewed the renal hazards of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the physiologic considerations for drug choices in patients at high risk for nephrotoxicity. Unfortunately, the most common indications for NSAIDs are inflammatory or noninflammatory pain syndromes that engender their chronic use. The NSAID will commonly be used not only in combination with medications such as diuretics, but also with caffeine and other analgesics. In 1984, a National Institutes of Health consensus conference on chronic analgesic nephropathy (causing 2% to 10% of end-stage renal disease) described the use of drug combinations in the over-the-counter marketplace as a significant community risk, and the industry responded by removing phenacetin from headache powders. 2 We have also learned from a case-control telephone survey of 554 adults with newly acquired renal disease that not only is the renal risk because of the

The role of apoptosis in the development of renal cortical tubular atrophy associated with healed experimental renal papillary necrosis

An animal model of chronic analgesic nephropathy, in which renal papillary necrosis was induced by the administration of a single injection of bromoethylamine 2-hydrobromide in male Sprague-Dawley rats, was used to investigate the pathogenesis of the atrophy of tubules that leads to cortical atrophy or 'scarring' in analgesic nephropathy. One of the major objectives was documentation of the participation of apoptosis, a distinctive mode of cell death, in the process of cortical tubular atrophy. Control and treated groups of animals were studied at 2 wks, and at subsequent monthly intervals up to 4 mths. At each time, light microscopy and ultrastructure were used to relate changes in cellular pathology to alterations in renal mass. Apoptosis was quantitated in paraffin sections, and autoradiographic identification of cells showing tritiated thymidine uptake was used as an indication of cell proliferation. In animals with total renal papillary necrosis (RPN), focal or diffuse cortical atrophy developed, the extent of which appeared to be proportional to the extent of the RPN. Renal mass was reduced only in those kidneys that developed extensive, diffuse lesions. Compensatory renal growth occurred in the areas of healthy tissue adjacent to the foci of atrophy, with both cellular hyperplasia and hypertrophy playing roles in its development. One of the prominent cellular events was the appearance of apoptotic cells and bodies, with invading intraepithelial macrophages involved in their phagocytosis and degradation. We propose that this form of cell death plays an important role in the pathogenesis of cortical atrophy. Current descriptions of the cortical lesions that occur in analgesic nephropathy refer to the changes as 'scars'. Although the focal lesions have a macroscopic appearance that resembles scars, the results of the present study indicate that usage of this terminology may be misleading, since scarring is often described after severe tissue injury or necrosis, which was not identified in the present study.

Abstracts

An animal model of chronic analgesic nephropathy, in which renal papillary necrosis was induced by the administration of a single injection of bromoethylamine 2-hydrobromide in male Sprague-Dawley rats, was used to investigate the pathogenesis of the atrophy of tubules that leads to cortical atrophy or 'scarring' in analgesic nephropathy. One of the major objectives was documentation of the participation of apoptosis, a distinctive mode of cell death, in the process of cortical tubular atrophy. Control and treated groups of animals were studied at 2 wks, and at subsequent monthly intervals up to 4 mths. At each time, light microscopy and ultrastructure were used to relate changes in cellular pathology to alterations in renal mass. Apoptosis was quantitated in paraffin sections, and autoradiographic identification of cells showing tritiated thymidine uptake was used as an indication of cell proliferation. In animals with total renal papillary necrosis (RPN), focal or diffuse cortical atrophy developed, the extent of which appeared to be proportional to the extent of the RPN. Renal mass was reduced only in those kidneys that developed extensive, diffuse lesions. Compensatory renal growth occurred in the areas of healthy tissue adjacent to the foci of atrophy, with both cellular hyperplasia and hypertrophy playing roles in its development. One of the prominent cellular events was the appearance of apoptotic cells and bodies, with invading intraepithelial macrophages involved in their phagocytosis and degradation. We propose that this form of cell death plays an important role in the pathogenesis of cortical atrophy. Current descriptions of the cortical lesions that occur in analgesic nephropathy refer to the changes as 'scars'. Although the focal lesions have a macroscopic appearance that resembles scars, the results of the present study indicate that usage of this terminology may be misleading, since scarring is often described after severe tissue injury or necrosis, which was not identified in the present study.