Case submitted by: David S. Priemer, MD1 (fellow), Jacquelynn T. Swan, MD2, and Carrie L. Phillips, MD1
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana1, and Hendricks Regional Hospital, Avon, Indiana2, USA
A 38-year-old woman presented to the Emergency Department following a generalized seizure that was preceded by at least several days of increasing confusion. She was a poor historian; however, her past medical history was significant for chronic substance abuse and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) associated vasculitis treated with systemic steroids four years prior to her most recent presentation. Tissue biopsy had not been previously performed. Initial laboratory tests were most remarkable for an elevated serum creatinine of 11.31 mg/dL, leukopenia (white blood cell count of 2.9 k/mm3), and neutropenia (1.3 k/mm3). Serologic studies were positive for p-ANCA but negative for cytoplasmic (c)-ANCA. Autoantibodies were elevated for myeloperoxidase (MPO) and anti-proteinase 3 (PR3). Anti-nuclear antibody (ANA) was measured at the upper limit of normal. Serum complement C3 and C4 levels were low at 59 mg/dL and 12 mg/dL, respectively. Titers for PLA2R and THSD7A were not determined. Remaining laboratory studies are tabulated below. The patient was admitted for renal replacement therapy. After five days of hemodialysis a renal biopsy was performed.
Table 1. Patient Laboratory Studies
|White blood cell count||5.4 k/mm3|
|Hemoglobin||8.8 GM/dL (L)|
|Calcium||8.4 mg/dL (L)|
|Phosphorus||6.6 mg/dL (H)|
|Blood Urea Nitrogen||70 mg/dL (H)|
|Creatinine||11.31 mg/dL (H)|
|Estimated glomerular filtration rate||4 mL/min/1.73m2 (H)|
|Glucose||H 107 mg/dL (H)|
|Urine specific gravity||1.010|
|Urine Protein||>500 mg/dL (H)|
|Urine Glucose||150 mg/dL (H)|
|Urine Red Blood Cells||50-100/high-power field (H)|
|Urine Hemoglobin||70 Ery/ÂµL (H)|
|Urine urobilinogen and bilirubin||Negative|
|Urine White Blood Cell Esterase, bacteria, and nitrites||Negative|
|C3 Complement||59 mg/dL (L)|
|C4 Complement||L 12 mg/dL (L)|
|Myeloperoxidase antibody||>8.0 Units (H)|
|Proteinase 3 antibody||0.6 Units (H)|
Abnormal values are indicated by H = high; L = low.
Renal biopsy findings:
At least 45 glomeruli were sampled in sections from formalin-fixed, paraffin-embedded renal tissue, of which 33 were obsolescent (73.3%). The remaining glomeruli showed variable mesangial matrix expansion but lacked nodularity. Glomerular capillary loops were remarkable for spikes and vacuoles (figure A) along basement membranes including some with segmental collapse and capsular adhesions (figure B). Crescents were not seen. Other findings included a significant degree of tubular atrophy and interstitial fibrosis (figure C) with monocellular interstitial inflammatory infiltrates.
Interpretation: The findings were consistent with membranous glomerulopathy, with secondary focal segmental glomerular sclerosis.Â Features diagnostic of active vasculitis were not seen.
The patientâs urine drug screen and blood toxicology were positive. Adulteration of which of the following drugs of abuse has been associated with this patientâs renal disease?
- gamma-Hydroxybutyric acid
- 3,4-Methylenedioxymethamphetamine (MDMA)
Answer:Â D. Cocaine, with adulteration by levamisole
- What is levamisole and what is its licit use?
- Why is levamisole used as an adulterant in cocaine?
- What are the adverse effects and clinical conditions associated with levamisole use?
- What are the pathologic findings that have been associated with levamisole-induced renal disease?
Levamisole is a synthetic imidazothiazole drug initially discovered in 19661. It was originally used as an antihelminthic drug in both humans and animals, as an immunomodulatory agent for rheumatoid arthritis, and also as adjuvant therapy for various cancers1-3. The most notable adverse effects of the medication at the time of its use were fevers and severe agranulocytosis4, and it is because of the latter that it was discontinued in the United States in the year 20005. Currently its only use in the United States is in veterinary medicine, where it is used as a dewormer in livestock6.
Due to similar physical properties, levamisole has been increasingly used as a cutting agent (adulterant) in cocaine. This is to the point where levamisole has been found in the majority of cocaine seized within the United States since 2009, and it has also been found in up to 76% of cocaine-positive urine samples in a recent prospective study5,7,8. Abuse of levamisole-laced cocaine has been associated with a variety of diseases distinct from those seen from cocaine use alone. These diseases include neutropenia/agranulocytosis, ANCA-associated necrotizing systemic vasculopathy, seizures, arthralgias, and fevers4,5,7,9,10. The most commonly cited clinical manifestation of levamisole-induced vasculitis is cutaneous, characterized by large hemorrhagic bullae and necrosis most commonly affecting the ears and cheeks. Laboratory findings frequently seen in the setting of levamisole-contaminated cocaine abuse include leukopenia, agranulocytosis, and positive serology for ANA, ANCA, and PR3 antibodies. Abuse of levamisole-contaminated cocaine has been recently implicated in the development of renal disease, most commonly characterized as a pauci-immune glomerulonephritis with crescent formation11-14. Associations with membranous glomerulopathy have been published but are limited to single case reports or relatively small collections of specimens.
In our patientâs case, she had a long-standing history of cocaine abuse and previously diagnosed ANCA-associated, levamisole-induced vasculitis prior to presenting with significant renal disease. Her laboratory studies were consistent with those seen as a manifestation of levamisole toxicity and exposure. The findings in her renal biopsy specimen are not associated with cocaine abuse alone, and therefore it was determined that they occurred as part of a continued spectrum of levamisole-induced disease. Crescents were not noted in our case, as has been reported in other cases of levamisole-induced glomerulopathy, and while this may represent a somewhat different disease process than those reported, it may also be due to chronic progression of her disease. This is evidenced by the limited number of non-sclerotic glomeruli in our specimen. The segmental scars in some glomeruli may be a result of âhealedâ fibrinoid necrosis (i.e., due to remote necrotizing glomerulonephritis in the setting of ANCA-associated vasculitis) due to levamisole exposure or perhaps another unidentified adulterant or drug of abuse such as heroine15.
Given the current high prevalence of levamisole use as an adulterant in cocaine, pathologic findings that may be associated with the adulterant may be important to recognize in forensic or hospital-based cases associated with drug abuse. Among these histopathologic findings may be glomerulopathic disease.
- Rossof AH, Philpot TR, Bunch RS, Letcher J. The high cost of levamisole for humans. N Engl J Med. 1991 Mar 7;324(10):701-2.
- Amery WK, Bruynseels JP. Levamisole, the story and the lessons. Int J Immunopharmacol. 1992 Apr;14(3):481-6.
- Wright V, Amos R. Do drugs change the course of rheumatoid arthritis? British Medical Journal. 1980;280(6219):964-966.
- Symoens J, Veys E, Mielants M, Pinals R. Adverse reactions to levamisole. Cancer Treat Rep. 1978 Nov;62(11):1721-30.
- Lee KC, Ladizinski B, Federman DG. Complications Associated With Use of Levamisole Contaminated Cocaine: An Emerging Public Health Challenge. Mayo Clinic Proceedings. 2012;87(6):581-586. doi:10.1016/j.mayocp.2012.03.010.
- Taylor, M. A.; Coop, R. L.; Wall, R. L. (2015). Veterinary Parasitology. John Wiley & Sons. p. 329
- Larocque A, Hoffman RS. Levamisole in cocaine: unexpected news from an old acquaintance. Clin Toxicol (Phila). 2012 Apr;50(4):231-41.
- Eiden C, PeyriÃ¨re H, Diot C, Mathieu O. Prevalence of levamisole and aminorexÂ in patients tested positive for cocaine in a French University Hospital. Clin Toxicol (Phila). 2015;53(7):604-8.
- Abdul-Karim R, Ryan C, Rangel C, Emmett M. Levamisole-induced vasculitis. Proceedings (Baylor University Medical Center). 2013;26(2):163-165.
- Roberts JA, ChÃ©vez-Barrios P. Levamisole-Induced Vasculitis: A CharacteristicÂ Cutaneous Vasculitis Associated With Levamisole-Adulterated Cocaine. Arch PatholÂ Lab Med. 2015 Aug;139(8):1058-61.
- Roca-Argente L, Moll-Guillen JL, EspÃ-Reig J, Blanes-Julia M, GarcÃa-MartÃnez AM, Pujol-Marco C, HernÃ¡ndez-Jaras J. Membranous glomerulonephritis and cellular crescents induced by levamisole-adulterated cocaine abuse: a case report. Ann Transl Med. 2015 Oct;3(18):271.
- Moinuddin I, Madhrira M, Bracamonte E, Thajudeen B, Sussman A. Membranous nephropathy with crescents associated with levamisole-induced MPO-ANCA vasculitis. Pathol Res Pract. 2016 Jul;212(7):650-3.
- Carrara C, Emili S, Lin M, Alpers CE. Necrotizing and crescentic glomerulonephritis with membranous nephropathy in a patient exposed to levamisole-adulterated cocaine. Clin Kidney J. 2016 Apr;9(2):234-8.
- Collister D, Sathianathan C, Ryz K, Karpinski M, Bernstein K, Gibson IW.ANCA Associated Vasculitis Secondary to Levamisole-Adultered Cocaine with Associated Membranous Nephropathy: A Case Series. Am J Nephrol. 2017;45(3):209-216.
- Jaffe JA, Kimmel PL. Chronic nephropathies of cocaine and heroin abuse: a critical review. Clin J Am Soc Nephrol. 2006 Jul;1(4):655-67.