CASE REPORT

The Effect of Chronic Renal Failure on the Benzoylecgonine Blood Level A Case Report Daniel A. Guillaud, MD,* Prentiss Jones, PhD,† and Joseph A. Prahlow, MD†‡

Abstract: Chronic renal failure results in reduced elimination of a variety of substances within the blood, including numerous drugs and their metabolites. This report describes a case of a man who died in jail, after less than 48 hours of being incarcerated, wherein postmortem toxicology testing revealed a blood benzoylecgonine level of 0.25 mg/L with no cocaine detected, suggesting possible recent cocaine use in jail. Autopsy and investigation revealed severe underlying cardiovascular disease and dialysis-dependent CRF, thus accounting for the elevated benzoylecgonine levels and allaying concerns that the man obtained and used cocaine in jail. Key Words: forensic, autopsy, toxicology, cocaine, benzoylecgonine, renal failure (Am J Forensic Med Pathol 2015;36: 84–87)

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hronic kidney disease (CKD) is defined as a glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 that persists for 3 months or more or the presence of kidney damage, including proteinuria, hematuria, or an anatomical abnormality.1 It usually begins with an asymptomatic period but has the potential to progress to end-stage renal disease (ESRD), where GFR is less than 15 mL/min per 1.73 m2 or the patient is dependent on dialysis.1 Chronic kidney disease is very prevalent with approximately 13.07% of the US population exhibiting some stage of the disease, according to the National Health and Nutrition Examination Surveys of 1999–2004.1 This results in a significant impact on the health care system because of the direct effects related not only to decreased GFR, but also to the many comorbidities that accompany CKD. With decreased renal function, patients are at risk for hypertension, accelerated cardiovascular disease, anemia, bone mineral metabolism disorders, metabolic acidosis, malnutrition, and electrolyte disturbances2; the severity of which increases with more advanced dysfunction.1 These comorbidities can have a devastating impact on patient health. In fact, it is more likely for patients with CKD to die of cardiovascular complications than to progress to established renal failure.1 In addition to these comorbidities, decreased renal function can also impair drug metabolism and elimination, as the majority of all drugs ultimately rely on the kidney.3 Important pathways such as chemical reduction, acetylation, and ester or peptide hydrolysis may be delayed with renal failure, resulting in the accumulation of drug metabolites in patients with renal insufficiency.3 Multiple

Manuscript received June 25, 2014; accepted January 3, 2015. From the *Indiana University School of Medicine, Indianapolis; and †The Medical Foundation; and Indiana ‡University School of Medicine–South Bend, South Bend, IN. The authors report no conflict of interest. Reprints: Joseph A. Prahlow, MD, The Medical Foundation, 530 N Lafayette Blvd, South Bend, IN 46601. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0195-7910/15/3602-0084 DOI: 10.1097/PAF.0000000000000151

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etiologies can be responsible for the development of CKD because of prerenal, intrarenal, or postrenal disruption.4 The majority of cases of CKD in the United States, however, result from diabetes mellitus, hypertension, or glomerular disease.2 Although these etiologies are the most prevalent, it is important to consider the role of drug abuse in development of ESRD, especially in younger patients.3 The link between drug abuse and renal failure has been confirmed in several studies.3 Opiate-related kidney disease is estimated to play a role in 5% to 6% of patients beginning treatment for ESRD, whereas cocaine has also been linked to renal disease with a 10-fold increase in relative risk for developing ESRD with cocaine abuse.3 Drug abuse may cause damage directly and be specific to a drug’s effects or may be caused indirectly through the action of drug abuse.3 Cocaine, for example, results directly in renal injury via changes in hemodynamics, matrix synthesis and degradation, oxidative damage, and induction of renal atherogenesis.5 Opiate use, on the other hand, may lead to transmission of HIV, resulting indirectly in HIV nephropathy.3 Both acute and chronic damage is also possible. Cocaine causes acute kidney injury via rhabdomyolysis with resultant myoglobinuria, malignant hypertension, or acute interstitial nephritis.3 Long-term use can produce focal glomerulosclerosis, immune complex glomerulonephritis, and ischemic arteriolitis.3 Hypertensive renal changes have also been identified in chronic cocaine abusers despite the absence of underlying hypertension or diabetes mellitus.3 This damage can lead to nonspecific findings including progressive nephropathy, hypertension, azotemia, and proteinuria.3,5 In addition, chronic renal failure (CRF) can be worsened by cocaineinduced hypertension.5 Cocaine is a drug of abuse derived from the leaves of the coca plant Erythroxylan coca. This plant is native to the Andes Mountains and is primarily grown in South America. Cocaine interferes with dopamine reuptake, increasing the amount of neurotransmitter at the synapse. The effect is stimulatory with the greatest impact on the cardiovascular and central nervous system.6,7 The vasoconstrictive and anesthetic properties make it a prime drug for surgery of the eye, nose, and throat, because of decreased bleeding. Street versions of the drug are abused for their euphoric effect and include cocaine hydrochloride, free base, and crack cocaine. With the introduction of crack, cocaine became one of the most abused drugs in America. Cocaine’s impact is substantial with more than 50,000 cocaine-related deaths within the last decade in the United States.8 These deaths may be directly or indirectly related to cocaine.9 Direct toxic effects of cocaine may lead to arrhythmias, myocardial infarction, cerebrovascular hemorrhage, seizure, hyperthermia, panic attacks, rupture of an existing aneurysm, or excited delirium.6 Chronic abuse can lead to natural death from related chronic disease such as atherosclerosis or cardiomegaly.7 Cocaine can be indirectly responsible for deaths because of violence or accidents. Approximately 50% of homicides in large cities are drug related.7 This high prevalence of cocaine-related deaths supports consideration of cocaine Am J Forensic Med Pathol • Volume 36, Number 2, June 2015

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involvement during death investigations; especially when death is sudden, unexpected, or apparently unnatural.7 In order to certify the cause of death as cocaine intoxication, one must review investigative findings, complete an autopsy that rules out trauma and natural disease, and identify, confirm, and quantify cocaine and/or metabolites such as benzoylecgonine (BE) in the blood.10,11 Unfortunately, isolated postmortem concentrations of cocaine and BE blood levels cannot predict toxicity,8 because virtually any level of the drug can potentially be lethal, and no minimal fatal concentration for cocaine has been established.12 The measurements of cocaine and its metabolites are affected by drug dosage, time elapsed from dose until death, and time elapsed from death until sample collection,8 resulting in physical and chemical differences between specimens collected at autopsy versus during life.7 Therefore, it is the qualitative presence of cocaine that becomes significant rather than quantitative analysis when attributing death to cocaine use.7,13 In cases where there is no other explanation for death, the cause of death may be ruled as the toxic effects of cocaine based on the information available and the fact that cocaine metabolites (notably BE) are present in the blood, even in the absence of measurable cocaine. Herein, we describe a case of a man who died in jail, after less than 48 hours of being incarcerated, wherein postmortem toxicology testing revealed a blood BE level of 0.25 mg/L with no cocaine detected, suggesting possible recent cocaine use in jail. Autopsy and investigation revealed severe underlying cardiovascular disease and dialysis-dependent CRF, thus accounting for the elevated BE levels and allaying concerns that the man obtained and used cocaine in jail.

CASE REPORT The patient, a 43-year-old man with a history of medical noncompliance, uncontrolled hypertension, and a 13-year history of hemodialysis-dependent renal failure, was found unresponsive in his jail cell. Resuscitation efforts failed, and the patient died. He was the only inmate in the cell, and he had been incarcerated for approximately 48 hours. His last hemodialysis appointment was 5 days prior, as he had refused dialysis 2 days prior to his incarceration. A medical examiner’s autopsy found a thin man with a body length of 70 inches and an estimated weight of 160 lb. External examination was unremarkable with no evidence of injury. On internal examination, the head and central nervous system revealed focal areas of mild cerebral artery atherosclerosis but were otherwise unremarkable. The cardiovascular system displayed focal areas of mild to moderate atherosclerosis within the intimal surface of the aorta. There was also marked cardiomegaly with a heart weight of 700 g accompanied by concentric left ventricular hypertrophy, measuring up to 2.3 cm. The coronary artery system was right predominant and free of atherosclerosis. The genitourinary system revealed shrunken kidneys with markedly pock-marked and granular subcapsular surfaces with numerous cysts, consistent with a history of CRF with ESRD and hemodialysis. The cortices were thin, and the calyces, pelves, and ureters contained rare stones bilaterally. The remainder of the internal examination was unremarkable. Microscopic examination of the heart revealed interstitial fibrosis, myocyte hypertrophy, and minimal coronary artery atherosclerosis. The lungs displayed emphysema and mild mixed bronchial inflammation. The kidneys showed evidence of arteriolosclerosis and ESRD. The remainder of the microscopic examination was unremarkable. Toxicology testing revealed a postmortem blood drug screen positive for tetrahydrocannabinol metabolite and for cocaine metabolite, BE, at a level of 0.25 mg/L, but no cocaine was detected © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Renal Failure and Benzoylecgonine Level

by gas chromatography/mass spectrometry. After further investigation of the BE level as presented below, the patient was declared to have died a natural death because of hypertensive and atherosclerotic cardiovascular disease. The toxicology results were initially alarming to investigators and the administration of the jail as they suggest the possibility of inmate access to cocaine during his jail stay. Upon further investigation at the facility, however, the possibility that the patient could have used cocaine during incarceration was refuted. The elevated BE levels can be explained by the existence of ESRD wherein BE levels are known to remain elevated long term. The presence of BE in blood does not indicate in this case that recent cocaine use (or an acute cocaine intoxication) occurred.

DISCUSSION This case brings to light the criteria necessary to declare a death as cocaine related and highlights the shortcomings and limitations of the toxicological tests available. It is recommended that to certify a death as cocaine related, the toxicological data should reveal the presence of both cocaine and its metabolite BE within blood.11 This establishes acute cocaine use. Because of the 0.5to 1.5-hour half-life of cocaine, even very high levels of cocaine would become undetectable within about 8 hours, or 6 to 7 halflives.9 Aside from establishing cocaine use within the past few hours, cocaine blood levels provide very little additional information concerning drug effect. A review of cocaine-related deaths in Bexar County, Texas, showed lethal cocaine levels from 0.01 to 78 mg/L.14 In addition to a wide lethal range, recreational and lethal cocaine blood concentrations overlap to the extent that there is no statistically significant difference.8,15 Because of these physiologic differences between individuals and changes within the blood after death, isolated postmortem cocaine concentrations in blood cannot predict toxicity or direct drug effect, and no minimum fatal concentration for cocaine can be established.7–9,12 Therefore, the mere presence of cocaine in the blood indicates a possible lethal dose and becomes a qualitative piece of evidence toward certifying a death as cocaine related.13 Because the effects of cocaine’s metabolites have not been established to directly affect the cause of death, the presence of only metabolites typically warrants certifying a death as natural, although their presence can be documented on the death certificate as a significant factor.11 There are exceptions, however, when the presence of BE alone is sufficient to declare a death as cocaine related.6,7,13,16 In the absence of measurable cocaine within postmortem blood samples, a death can still be ruled as being caused by cocaine toxicity, so long as metabolites are present in the blood, and there is no other explanation for death.6,12 This principle is evident in a study on a group of individuals where cocaine appeared to be the cause of death. Analysis revealed that 35% had only BE found in the blood.16 It is common to encounter moderate concentrations (0.2–1.5 mg/L) of BE without the presence of cocaine.12 In the absence of other pathology, the lack of cocaine within the blood can be explained by the redistribution of cocaine and its continued metabolism to BE, which occurs postmortem. Other physiologic changes that occur after death such as hematocrit, pH, temperature, and enzyme activity changes also alter measureable drug concentrations.7,12 The result is that postmortem cocaine and metabolite concentrations may not reflect perimortem concentrations.12 Even samples collected from the same individual at different times can show unpredictable change in either direction.12 There are, however, explanations for these changes. Postmortem levels of cocaine may increase as cocaine is released from sequestration in tissues such as heart.12 Levels may also appear elevated if central blood samples are taken because all basic drugs www.amjforensicmedicine.com

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redistribute from the lungs into the left ventricle, thus increasing their concentration.9 For this reason, peripheral samples are preferred. Of more significance to the case presented are situations that can lead to a decrease in cocaine levels postmortem. In living individuals, cocaine has low renal clearance of about 27 mL/min and is largely eliminated via biotransformation.5 Therefore, CRF is expected to have very little impact on the metabolism of cocaine. Only a very small percentage of cocaine is eliminated unchanged in the urine, and nonrenal mechanisms account for 98.5% of total cocaine clearance.17 This nonrenal cocaine clearance occurs via plasma and liver cholinesterases to produce the water-soluble metabolites BE and ethyl methylecgonine, which can then be excreted in the urine.5,7,9 In addition, a small portion of cocaine is metabolized to norcocaine via the cytochrome P450 system in the liver.5 Postmortem, the plasma cholinesterases continue to function, further decreasing blood cocaine concentrations and increasing blood BE concentrations if samples are unpreserved or left at room temperature, with the most drastic changes in blood levels likely happening immediately postmortem.9,12,15 Within hours, an unpreserved, room-temperature blood sample from a recent user may already hydrolyze cocaine to undetectable levels and show only BE.7,13 In this situation, the only evidence of cocaine intoxication is the presence of the metabolites. To combat the further degradation of cocaine by plasma esterases, a preservative such as sodium fluoride should be used with a target concentration of 5 to 10 mg/mL. This effectively inhibits the enzyme-mediated hydrolysis of cocaine.9 Refrigeration at 4°C to 5°C will further slow the enzymatic conversion, and freezing at −20C will stop enzymatic conversion. Even with proper sample collection and storage, a portion of cocaine is still broken down via spontaneous pH-dependent hydrolysis.9,13 With this continuous degradation in mind, appropriately collected samples with preservative should be expected to remain stable for 1 week if refrigerated and at least 3 months if frozen.9 Collecting samples from other tissues for comparison is ideal and provides further information on cocaine intoxication beyond blood levels. Brain tissue can be particularly useful. Benzoylecgonine cannot readily cross the blood-brain barrier, so BE formed in the brain remains there until metabolized18 and provides an excellent sample to evaluate drug levels and represent the pharmacological effect on the brain.7,9,10,19 Comparing cocaine-to-BE ratios within brain tissue can provide insight concerning acute versus chronic exposure.9,19 This practice demands the proper resources be available to the medical examiner as well as collection of brain tissue within 6 to 12 hours of death.9 The circumstances of the case presented did not allow this type of analysis of brain tissue. Review of the autopsy findings in the case presented reveals that there are indeed other possible explanations for the patient’s death. Therefore, given that only cocaine metabolites were present, death due to cocaine intoxication was ruled out. Given the incarcerated nature of the patient, however, the significance of elevated BE levels still demanded interpretation. The 0.5- to 1.5-hour half-life of cocaine is significantly shorter than the 5- to 6-hour half-life of BE.9,20 Therefore, BE concentrations will increase as cocaine levels drop, but remain elevated even after cocaine is no longer detectable.7 For this reason, analysis of the cocaine-to-BE ratio can provide useful information. High cocaine-to-BE ratios provide evidence of recent exposure, whereas low cocaine-to-BE ratios suggest more remote use.9 Once all of the cocaine is metabolized, the remaining BE is an indicator that cocaine use occurred, but not necessarily that day.7 Given the known half-life of BE, it seems reasonable that one could use blood or urine levels to estimate the time of exposure. Unfortunately, critical variables such as dose amount and frequency of dosing are usually unknown.11,20 In addition,

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biological half-lives may vary considerably.11 Data by Jufer et al7,21,22 suggest that cocaine may accumulate within body tissues through chronic use and be released slowly back into the bloodstream.7,21,22 This conclusion was based on observation of a prolonged terminal elimination phase for cocaine metabolites in which half-life estimates ranged from 14 to 52 hours versus the standard 5 to 6 hours.20,21 Given the wide range of elimination rates, the metabolite’s presence can serve as a marker of recent cocaine use for several days after a single dose, but may be present for a week or longer in chronic users.7 Therefore, it is difficult to estimate when the drug was taken. Hair or nail analysis can help qualitatively establish if cocaine use was chronic.9 The cutoff blood level for BE established by the National Institute on Drug Abuse with living patients in mind is 0.15 mg/L.20 Our patient had a positive serum level of 0.25 mg/L. Because we have no information on dose taken, dose frequency, or status of chronic use, we cannot estimate when the cocaine was taken. It remains possible that cocaine was used in jail during incarceration or chronically prior to arrival. The possibility for use prior to incarceration is supported by a study in 1996 that showed 24% of convicted inmates used some form of cocaine within the month prior to incarceration.23 Use in jail is supported by a 1998 study that revealed 10% of drug tests conducted on inmates in the United States were positive for 1 or more drugs.23 Regardless of this statistic, it was very alarming to investigators and jail administration when the blood levels were revealed, as the BE levels suggested possible recent use. The facility denied any possibility of inmate cocaine use. Norris et al24 reported that 30% of their hemodialysis population had a history of significant cocaine use prior to the initiation of dialysis. They also noted a strong association between cocaine use and an ESRD diagnosis of hypertension-related ESRD. Further research revealed that CRF results in declining kidney function and impaired renal excretion of many drugs and their metabolites.25 As cocaine is largely cleared nonrenally, CRF is not expected to affect cocaine metabolism.17 However, because the kidney is primarily responsible for elimination of drug metabolites, a decrease in renal clearance leads to their accumulation and increases the time they are detectable.25 As the cocaine metabolite BE is water soluble and excreted unchanged in the urine,5 it is reasonable to infer that the decrease in GFR associated with CKD would lead to a decrease in clearance of BE and an increased level and duration of detectability within the blood. This is supported by Isenschmid et al when examining 75 decedents with CKD, 23 (31%) of whom were found to have elevated BE levels within the blood, whereas only 4 had parent cocaine detected.26 A comparison in decedents with normal renal function revealed that cocaine was frequently detected, and BE levels were much lower, suggesting that in patients with CKD, BE may accumulate to unusually high concentration.26 A literature search revealed no additional case reports or case series regarding the impact of CKD and elimination of BE from the blood. Using the above findings combined with our patient’s alleged inability to obtain cocaine while incarcerated, his absence of cocaine within the blood, lack of evidence at the scene, and his other existing pathology, it was determined that the patient’s death was related to his severe natural disease and that the BE level was due to CRF and had no relation to recent acute cocaine exposure. Based on the fact that the inmate was reportedly a chronic cocaine user, it is reasonable to conclude that his cardiomegaly was, at least in part, related to chronic cocaine use6,8; however, this fact does not change the fact that the death is considered a natural death, as deaths related to chronic drug use are, by convention, considered natural deaths.7 © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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CONCLUSIONS Cocaine is frequently present in postmortem toxicology tests performed in conjunction with medicolegal/forensic autopsies. Whether cocaine is implicated as a cause of death depends on numerous factors, including circumstances and postmortem levels of cocaine and its metabolites. Although certifying a death as being caused by the toxic effects of cocaine usually requires the presence of cocaine within postmortem blood samples, occasional cases occur where death is attributed to cocaine when only cocaine metabolites are identified in postmortem blood. This can cause great concern, such as in the case described, because the presence of BE within postmortem blood samples usually indicates relatively recent cocaine use. However, CRF can result in reduced elimination time of BE; consequently, the presence of BE in the context of CRF does not necessarily indicate recent cocaine usage. REFERENCES 1. National Collaborating Center for Chronic Conditions. Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. London, UK: Royal College of Physicians; 2008. 2. White JJ. Chronic kidney disease. In: Internal Medicine Essentials for Students. Alguire PC, DeFer TM, Fagan MJ, et al., eds. Philadelphia, PA: American College of Physicians Press; 2011. 3. Kunis CL, Aggarwal N, Appel GB. Clinical nephrotoxins; renal injury from drugs and chemicals. Illicit Drug Abuse and Renal Disease. DeBroe ME, Porter GA, Bennett WM, et al., eds. New York, NY: Springer; 2008:987. 4. Frayha N, Hanes D. National Medical Series for Independent Study: Medicine. Wolfsthal SD, eds. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. 5. Chike M, Nzerue M, Karlene Hewan-Lowe M, et al. Cocaine and the kidney: a synthesis of pathophysiologic and clinical perspectives. Am J Kidney Dis. 2000;35(5):783–795. 6. Prahlow J. Drug-related and toxin-related deaths. Forensic Pathology for Police, Death Investigators, Attorneys, and Forensic Scientists. New York: Humana Press; 2010:275–277. 7. Stephens BG. Investigation of Deaths from Drug Abuse, in Medicolegal Investigation of Death. Spitz WU, ed. Springfield, IL: Charles C. Thomas Publisher, Ltd; 2006:1166–1188. 8. Karch SB, Stephens B, Ho CH. Relating cocaine blood concentrations to toxicity-an autopsy study of 99 cases. J Forensic Sci. 1998;43(1):41–45. 9. Stephens BG, et al. Criteria for the interpretation of cocaine levels in human biological samples and their relation to the cause of death. Am J Forensic Med Pathol. 2004;25(1):1–10.

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10. Bertol E, et al. Cocaine-related deaths: an enigma still under investigation. Forensic Sci Int. 2008;176:121–123. 11. Stephens BG, et al. National Association of Medical Examiners position paper on the certification of cocaine-related deaths. Am J Forensic Med Pathol. 2004;25(1):11–13. 12. Logan BK, Smirnow D, Gullberg RG. Lack of predictable site-dependent differences and time-dependent changes in postmortem concentrations of cocaine, benzoylecgonine, and cocaethylene in humans. J Anal Toxicol. 1997;20:23–31. 13. Dolinak D, Matshes E, Lew E. Toxicology. In: Forensic Pathology: Principles and Practice. Listewnik M, ed. Burlington, MA: Elsevier Academic Press; 2005:494–495. 14. Molina DK, Hargrove VM. Fatal cocaine interactions: a review of cocaine-related deaths in Bexar County, Texas. Am J Forensic Med Pathol. 2011;32(1):71–77. 15. Jenkins AJ, et al. The interpretation of cocaine and benzoylecgonine concentrations in postmortem cases. Forensic Sci Int. 1999;101:17–25. 16. Lora-Tamayo C, Tena T, Rodriguez A. Cocaine-related deaths. J Chromatogr A. 1994;674:217–224. 17. Chow MJ, et al. Kinetics of cocaine distribution, elimination, and chronotropic effects. Clin Pharmacol Ther. 1985;38(3):318–324. 18. Misra AL, et al. Estimation and disposition of [3H]-benzoylecgonine and pharmacological activity of some cocaine metabolites. J Pharm Pharmacol. 1975;27(10):784–786. 19. Spiehler VR, Reed D. Brain concentrations of cocaine and benzoylecgonine in fatal cases. J Forensic Sci. 1985;30(4):1003–1011. 20. Karch SB. Interpreting cocaine blood levels. In: The Pathalogy of Drug Abuse. Boca Raton, FL: CRC Press, Inc; 1993:38–42. 21. Moeller MR, Kraemer T. Drugs of abuse monitoring in blood for control of driving under the influence drugs. Ther Drug Monit. 2002;24:210–221. 22. Jufer R, et al. Elimination of cocaine and metabolites in plasma, saliva, and urine following repeated oral administration to human volunteers. J Anal Toxicol. 2000;24(7):467–477. 23. Wilson DJ. Drug use, testing, and treatment in jails. Bureau of Justice Statistics Special Report. Washington, DC; 2000:1–12. 24. Norris KC, Thornhill-Joynes M, Tareen N. Cocaine use and chronic renal failure. Semin Nephrol. 2001;21(4):362–366. 25. Dowling TC. Drug metabolism considerations in patients with chronic kidney disease. J Pharm Pract. 2002;15(5):419–427. 26. Isenschmid DS, Smith GM, Bradford HR, et al. Unusually High Blood Benzoylecgonine Concentration in Cases With Renal Failure. The International Association of Forensic Toxicologists. Albuquerque, NM: 1998.

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The effect of chronic renal failure on the benzoylecgonine blood level: a case report.

Chronic renal failure results in reduced elimination of a variety of substances within the blood, including numerous drugs and their metabolites. This...
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