Can renal failure cause drug toxicity?
Acute renal failure (ARF) is defined as a rapid loss of renal function due to damage to the kidneys. This results in electrolyte and acid-base abnormalities and retention of nitrogenous waste products, such as urea and creatinine.
Patients with ARF are often asymptomatic and are diagnosed by observed elevations in blood urea nitrogen (BUN) and serum creatinine (SCr) levels. Common symptoms of ARF include anorexia, fatigue, mental status changes, nausea, vomiting, and pruritus. Seizures can occur if BUN levels are extremely high, and shortness of breath can result if volume overload is present.1 However, alterations in urine volume may be the only symptom that patients notice. Populations most at risk include the elderly and those with underlying renal insufficiency. Conditions that compromise renal blood flow or alter effective circulatory volume--such as bilateral renal artery stenosis, cirrhosis, nephrotic syndrome, or congestive heart failure--are considered risk factors for ARF. Incidence and Reporting of ARF The incidence of ARF, although relatively common, is difficult to define, and the incidence of drug-induced renal failure (DIRF) is even more difficult to ascertain. Current information suggests that ARF accounts for 1% of hospital admissions, implicating occurrence in the outpatient setting, and occurs in 2% to 5% of in-hospital patients. For hospitalized patients in the intensive care unit (ICU), the occurrence rate is 1% to 25%, with a 15% occurrence for patients undergoing cardiopulmonary bypass.1-4 Worldwide, the reported incidence of ARF in critical illness is 1% to 25%, with 3.4% to 4.9% of patients requiring renal replacement therapy (RRT).3 DIRF occurs in 18% to 27% of hospitalized patients with ARF, and 20% of hospital admissions for ARF are reportedly caused by drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs).5 There are several explanations for the lack of an accurate incidence of ARF in the population. First, there is no universally accepted clinical definition for ARF. Historically, most definitions have relied on an increase in the concentration of SCr (e.g., >0.5 mg/dL or 25%). A recent review of the epidemiology of ARF revealed that approximately 35 definitions exist in the medical literature.3 With such a variety of definitions, the range may widen for those definitions using modest increases in SCr or narrow for those studies that use tighter criteria to define ARF, such as the need for RRT. The Acute Dialysis Quality Initiative (ADQI), a group composed of nephrologists and intensivists with expertise in renal disease, recently proposed the RIFLE criteria for acute renal dysfunction. The RIFLE criteria evaluate severity and outcome of ARF. The severity classes (Risk, Injury, and F ailure) are based on the degree of change in urine output or SCr, and the outcome classes (Loss and End-Stage Kidney Disease) are based on the duration of kidney function loss.6 Several recent studies have begun using the RIFLE criteria. One major limitation they have encountered is that urine output cannot be accurately assessed without a urinary catheter, and use of diuretics, which increase urine output, decreases the validity of this measurement. Despite these limitations, the RIFLE criteria will provide a more accurate determination of the incidence not only of ARF but of DIRF as well.6 Determining the incidence of DIRF is even more difficult, particularly in the community, because mild changes in renal function often go unrecognized and unreported. Furthermore, in-hospital occurrence rates are low, due to both underrecognition and underreporting. Not all hospitals actively report adverse drug reactions, and most data, if collected, remain unpublished. Morbidity and Mortality The mean age at onset of ARF is approximately 67 years.7 In a recent prospective study identifying 1,738 patients with an increase in plasma urea or renal dysfunction that required dialysis, the median age was 67 years, and the mean length of stay in the ICU was 10 days.8 The mortality rate for patients with ARF is 23% to 80%, and this rate increases to 57% to 80% in patients requiring RRT. Hospital mortality for critically ill patients with ARF requiring RRT is approximately 60% to 70%.3 As with incidence data for ARF, mortality data for ARF are inaccurate due to the lack of a universally accepted definition for the condition and the disparate patient populations that have been studied. Most patients recover from ARF by 90 days, with 60% to 70% of patients recovering without the need for RRT. Patients with normal renal function prior to the first episode of ARF have a lower likelihood of needing long-term RRT.9 Types of ARF There are three types of ARF--prerenal, intrinsic, and postrenal ARF--which are classified based on underlying causes. Although there are multiple pathophysiologic causes for each type of ARF, drugs are common precipitating factors for each category. Prerenal ARF accounts for 40% to 70% of cases and results from decreased perfusion to the kidney. It may be caused by decreased intravascular volume due to blood loss, dehydration, or disease states such as congestive heart failure, hypotension, and liver failure, which result in decreased effective blood volume. Pre- and postglomerular arteriolar resistance is responsible for maintaining renal perfusion and glomerular filtration rate. Preglomerular (afferent) vasodilation and post-glomerular (efferent) vasoconstriction are controlled by prostaglandins and angiotensin II, respectively. Interruption of these pathways by drugs such as NSAIDs and angiotensin-converting enzyme (ACE) inhibitors results in renal hypoperfusion. Patients with underlying disease, such as the elderly and those with hypotension and dehydration, are at particular risk for DIRF.1,4,5 Considering the availability of NSAIDs and the growing size of the aging population, the risk of developing NSAID-induced renal failure is quite high. Intrinsic ARF accounts for 10% to 50% of ARFcases and results from damage to the kidney tissue. Various inflammatory diseases, such as systemic lupus erythematosus, can result in glomerulonephritis. Interstitial nephritis results from inflammation of the renal interstitium and tubules and can be caused by infections, immune-mediated diseases such as sarcoidosis and lymphomas, and drugs. Drugs most often implicated in the development of interstitial nephritis include certain antibiotics, antivirals, and immunosuppressants.4,10 Renal tubular injury usually results from ischemia or drugs. The tubules have an inherently high-energy demand due to active transport mechanisms and metabolic processes. This makes the tubules particularly sensitive to decreases in oxygen. Drugs such as amphotericin B upset the balance between oxygen demand and supply, which results in tubular damage.5,10 Other drugs, such as aminoglycosides, radiocontrast media, and heavy metals, become concentrated in the kidney and cause a direct toxic effect, usually in a dose-dependent manner. 4,5,10 Postrenal ARF accounts for only 10% of ARF cases and results from obstruction within the urinary tract that prevents the outflow and elimination of urine.4 The obstruction must involve both kidneys in order for ARF to develop.1 Patients at risk for postrenal ARF include those with malignancy, prostate disease, and bladder-outlet obstruction. Drugs such as acyclovir and methotrexate can cause crystal deposition in the tubules, which can occur when a patient is dehydrated. Drugs with low solubility may form crystals, causing obstruction of urine output and subsequent renal failure. NSAIDs Show Each year, up to 5% of people who take NSAIDs will develop renal toxicity, resulting in hospital admissions and an increase in health care spending.1 ACE inhibitors and angiotensin II receptor blockers are another frequent cause of ARF, especially in patients with severe renal artery stenosis or chronic kidney disease and in those hospitalized for congestive heart failure. Current guidelines recommend ACE inhibitors for patients with chronic kidney disease and systolic heart failure because of their proven benefits on morbidity and mortality;13 however, low doses should be used initially, and renal function should be monitored frequently.
Radiocontrast Dye
Summary DIRF is a serious, and often preventable, disease associated with significant morbidity and high health care costs. Drugs are often the culprit, and they range from commonly used over-the-counter analgesics to immunosuppressants and chemotherapeutic agents. As more and more drugs are introduced into the market without a clearly defined adverse drug reaction profile, recognition and reporting of potential adverse drug reactions, including nephrotoxicity, are becoming more important than ever. The FDA released a comprehensive statement early this year committing to a new initiative focusing on drug safety,19 including improving methods of surveillance to identify unforeseen drug toxicity. 1. Mueller BA. Acute renal failure. In: Pharmacotherapy. 6th ed. New York, NY: McGraw-Hill; 2005;781-90. 2. Gill N, Nally JV Jr, Fatica RA. Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management. Chest. 2005;128:2847-2863. 3. Uchino S. The epidemiology of acute renal failure in the world. Curr Opin Crit Care. 2006;12:538-543. 4. Hilton R. Acute renal failure. BMJ. 2006;333:786-790. 5. Nolin TD, Himmelfarb J, Matzke GR. Drug-induced kidney disease. In: Pharmacotherapy. 6th ed. New York, NY: McGraw-Hill; 2005;871-87. 6. Hoste E, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care. 2006;12:531-537. 7. Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care. 2006;12:557-560. 8. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818. 9. Bagshaw SM. The long-term outcome after acute renal failure. Curr Opin Crit Care. 2006;12:561-566. 10. Schetz M, Dasta J, Goldstein S, Golper T. Drug-induced acute kidney injury. Curr Opin Crit Care. 2005;11:555-565. 11. Mene P, Pugliese F, Patrano C. The effects of nonsteroidal anti-inflammatory drugs on human hypertensive vascular disease. Semin Nephrol. 1995;15:244-252. 12. Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med. 2002;69:289-290,293-294,296-297. 13. Chobanian AV, Bakris GL, Black HR. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206-1252. 14. Swan SK. Aminoglycoside nephrotoxicity. Semin Nephrol. 1997;17:27-33. 15. Fry AC, Farrington K. Management of acute renal failure. Postgrad Med J. 2006;82:106-116. 16. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006;354:379-386. 17. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291:2328-2334. 18. Lin J, Bonventre JV. Prevention of radiocontrast nephropathy. Curr Opin Nephrol Hypertens. 2005;14:105-110. 19. The future of drug safety--promoting and protecting the health of the public: FDA's response to the Institute of Medicine's 2006 report. Released January 30, 2007. Available at: www.fda.gov/oc/reports/iom013007.html. What drugs cause renal toxicity?Most street drugs, including heroin, cocaine and ecstasy can cause high blood pressure, stroke, heart failure and even death, in some cases from only one use. Cocaine, heroin and amphetamines also can cause kidney damage.
How does renal failure affect excretion of drugs?Since severe renal disease causes a reduction in the plasma protein binding of many drugs, the metabolic clearance of such drugs will be increased.
Which drugs are affected by renal failure?What Meds Might Hurt My Kidneys?. Antibiotics.. Diuretics.. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Proton Pump Inhibitors (PPIs). Supplements.. Laxatives.. If You Have Kidney Disease, Other Medications Can Be Harmful.. Why are kidneys vulnerable to drug toxicity?Renal tubular cells, in particular proximal tubule cells, are vulnerable to the toxic effects of drugs because their role in concentrating and reabsorbing glomerular filtrate exposes them to high levels of circulating toxins.
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