The potential role of complements in cocaine-induced thrombotic microangiopathy

The potential role of complements in cocaine-induced thrombotic microangiopathy Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular injury and occlusion resulting in tis- sue ischemia and dysfunction. TMA occurs in a variety of settings including cocaine use. Although cocaine is widely used in the United States, cocaine-associated TMA is only rarely reported. Therefore, other factors may predispose cocaine users to the development of TMA. Emerging evidence indicates that cocaine activates complements. Therefore, complement activa- tion may contribute to the development of cocaine-induced TMA. Here, we report a cocaine user who presented with renal failure. Renal biopsy demonstrated TMA. Laboratory tests revealed reduced serum complement C3 and normal complement C4 levels indicative of alternative complement activation. We postulate that complement activation is involved in the pathogenesis of cocaine-induced TMA. Key words: cocaine, complements, endothelial injury, thrombotic microangiopathy Introduction factor. Accumulating evidence indicates that cocaine and its Cocaine use remains a serious public health concern. Although adulterant levamisole may also activate complements [2–4]. cocaine can adversely affect the function of almost every organ Increased complement activity may cause endothelial injury system, the effects of cocaine on the vasculature including and thrombotic microangiopathy (TMA) [5, 6]. those of the kidney, the coagulation system and complements Cocaine use may cause kidney injury secondary to ischemia, are of particular interest to this report [1]. Cocaine causes endo- infarction, rhabdomyolysis, malignant hypertension and TMA. thelial dysfunction characterized by increased endothelin-1 Although cocaine is in widespread use in the United States, (vasoconstrictor) and reduced nitric oxide (vasodilator) release, cocaine-induced TMA is only rarely observed [7–9]. Therefore, thereby promoting vasoconstriction. Cocaine stimulates plate- other factors such as increased complement activity may pre- let activation and aggregation. It further promotes coagulation dispose cocaine users to TMA. Here, we report a middle-aged by increasing the activity of plasminogen activator inhibitor cocaine user who developed TMA accompanied by complement and raising the plasma levels of fibrinogen and von Willebrand abnormalities suggestive of alternative complement activation. Received: August 21, 2016. Editorial decision: May 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Complements in cocaine-induced TMA | 27 We postulate that complement activation is involved in the In all, 11 glomeruli appeared bloodless and demonstrated tuft pathogenesis of cocaine-induced TMA. wrinkling as well as focal and segmental sclerosis. There were severe (80%) interstitial fibrosis and tubular atrophy. There was severe diffuse acute tubular epithelial cell injury. Arteries dem- onstrated moderate arteriosclerosis with foci of superimposed Case presentation edematous intimal expansion resulting in luminal narrowing or A 54-year-old man with a history of polysubstance abuse pre- occlusion (Figure 1A and B). Arterioles showed hyperplastic sented with altered mental status. His past medical history was arteriolosclerosis (Figure 1C). Direct immunofluorescence notable for treatment-naı¨ve hepatitis C infection. Family history microscopy showed no immunoreactants. Ultrastructural was notable for a sister who was diagnosed with renal failure of examination of glomeruli revealed subendothelial widening by obscure etiology requiring dialysis at the age of 45 years. On finely granular and fibrillar material. The hospital course was examination, the patient was found to be afebrile, drowsy and notable for lack of renal recovery and uremia resulting in initia- hypertensive (172/110 mmHg). Jugular veins were distended. tion of hemodialysis. Considering the patient’s psychosocial There were crackles at the lung bases. Blood tests revealed crea- status and the severity of renal fibrosis, eculizumab therapy tinine 16.0 mg/dL, blood urea nitrogen 99 mg/dL, hemoglobin was not considered. The patient was discharged from the hospi- 11.3 g/dL, platelets 222 000/mm , LDH 907 (84–246 IU/L) and hap- tal to receive hemodialysis in a dialysis center in the toglobin 171 (30–200 mg/dL). Urinalysis showed proteinuria. A community. blood film revealed rare schistocytes. Random urine protein-to- creatinine ratio was 1.9. Urine toxicology revealed cocaine and its metabolites. Routine blood and urine cultures showed no Discussion growth. Serologic tests showed reduced complement C3 level of 71 (90–180 mg/dL) and normal C4 level of 32 (10–40 mg/dL). C3 Here, we report a cocaine user who developed TMA. TMA is a hypocomplementemia persisted throughout hospitalization. rare complication of cocaine use. Gu and Herrera observed his- There were no antibodies against HIV 1/2. Ultrasonography topathological features of TMA in 0.9% of 2750 kidney biopsies showed echogenic kidneys measuring 9.8 cm (right) and 10.3 cm [7]. They noted TMA associated with cocaine use and severe (left). A renal biopsy was performed 9 days following admission. hypertension in only 2 (0.07%) biopsies. The authors argued that It contained 62 glomeruli, 51 of which showed global sclerosis. the presence of severe hypertension alone does not appear to Fig. 1. Vascular histopathology. (A) An artery in the kidney showing luminal occlusion secondary to edematous intimal expansion (arrow) (hematoxylin and eosin stain). (B) Same artery as (A), demonstrating the absence of elastic fibers in the expanded intima (arrow) (Verhoeff’s Van Gieson elastin stain). (C) An arteriole demon- strating onion skin-like smooth muscle cell hyperplasia (hyperplastic arteriolopathy) (arrow) (periodic acid–Schiff stain). Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018 28 | A. Dejman et al. be sufficient for the development of TMA associated with infection as the cause of alternative complement activation in cocaine use. Similar to our case, neither case demonstrated our case. In conclusion, we argue that alternative complement marked anemia or absolute thrombocytopenia. Volcy et al. activation induced by cocaine and its adulterant levamisole reported a 38-year-old woman who presented with renal failure can cause TMA. along with hematological and histopathological features of TMA following inhalation of crack cocaine [8]. Balaguer et al. Conflict of interest statement reported a 22-year-old woman with a history of hepatitis C infection who developed acute hepatitis and renal failure fol- None declared. lowing ethanol and intravenous cocaine use [9]. They diagnosed TMA based on clinical and hematological findings. References Because the vast majority of cocaine users do not develop TMA, there must be hitherto poorly understood contributing 1. Schwartz BG, Rezkalla S, Kloner RA. Cardiovascular effects factor(s) that are crucial for the development of cocaine- of cocaine. Circulation 2010; 122: 2558–2569 induced TMA. Much is known about the role of complements in 2. Tanhehco EJ, Yasojima K, McGeer PL et al. Acute cocaine the pathogenesis of atypical hemolytic–uremic syndrome exposure up-regulates complement expression in rabbit (aHUS), which is a life-threatening form of TMA [5]. In aHUS, heart. J Pharmacol Exp Ther 2000; 292: 201–208 loss-of-function mutations affecting complement regulatory 3. Magro CM, Wang X. Cocaine-associated retiform purpura: genes lead to increased complement activity and complement- a C5b-9-mediated microangiopathy syndrome associated with mediated endothelial injury. Conditions that further augment enhanced apoptosis and high levels of intercellular adhesion complement activity (complement amplifying conditions) or molecule-1 expression. Am J Dermatopathol 2013; 35: 722–730 disturb endothelial homeostasis may result in severe microvas- 4. Kondo M, Kato H, Masuda M. Levamisole and serum comple- cular injury and thrombosis in genetically susceptible individu- ment. N Engl J Med 1978; 298: 1146 als [10]. Emerging evidence indicates that cocaine and 5. Nayer A, Asif A. Atypical hemolytic-uremic syndrome: levamisole (a cocaine adulterant) activate the complement sys- a clinical review. Am J Ther 2016; 23: e151–e158 tem. Tanhehco et al. showed that cocaine increased the gene 6. Mathew RO, Nayer A, Asif A. The endothelium as the com- expression of several complement components and the protein mon denominator in malignant hypertension and throm- expression of the terminal complement complex C5b-9 in the botic microangiopathy. J Am Soc Hypertens 2016; 10: 352–359 rabbit heart [2]. Magro et al. reported extensive vascular C5b-9 7. Gu X, Herrera GA. Thrombotic microangiopathy in cocaine deposition in cocaine-induced retiform purpura that is charac- abuse-associated malignant hypertension: report of 2 cases terized by skin necrosis secondary to cutaneous TMA [3]. Duran  with review of the literature. Arch Pathol Lab Med 2007; 131: et al. reported a 28-year-old man with complement factor H defi- 1817–1820 ciency who developed TMA (aHUS) triggered by cocaine use [11]. 8. Volcy J, Nzerue CM, Oderinde A et al. Cocaine-induced acute renal Kondo et al. explored the effects of levamisole on complements failure, hemolysis, and thrombocytopenia mimicking thrombotic in human subjects [4]. They demonstrated that levamisole led thrombocytopenic purpura. Am J Kidney Dis 2000; 35: E3 to complement activation via both classical and alternative 9. Balaguer F, Fernandez J, Lozano M et al. Cocaine-induced pathways. Therefore, we speculate that cocaine-induced com- acute hepatitis and thrombotic microangiopathy. JAMA plement activation can lead to microvascular injury and throm- 2005; 293: 797–798 bosis in genetically susceptible individuals. 10. Asif A, Nayer A, Haas CS. Atypical hemolytic uremic syn- Our patient had a history of hepatitis C infection. The drome in the setting of complement-amplifying conditions: serum C3 protein level can be reduced in patients chronically case reports and a review of the evidence for treatment with infected with hepatitis C compared with healthy individuals. eculizumab. J Nephrol. 2017; 30: 347–362 This is in part secondary to hepatitis C-induced suppression of 11. Duran  CE, Blasco M, Maduell F et al. Rescue therapy with ecu- C3 production in hepatocytes [12]. However, several reports lizumab in a transplant recipient with atypical haemolytic- have shown that hepatitis C infection also reduces comple- uraemic syndrome. Clin Kidney J 2012; 5: 28–30 ment C4 expression and serum levels. Therefore, we believe 12. Mazumdar B, Kim H, Meyer K et al. Hepatitis C virus proteins that normal serum C4 levels argue against hepatitis C inhibit C3 complement production. JVirol 2012; 86: 2221–2228 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

The potential role of complements in cocaine-induced thrombotic microangiopathy

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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2048-8505
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2048-8513
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Abstract

Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular injury and occlusion resulting in tis- sue ischemia and dysfunction. TMA occurs in a variety of settings including cocaine use. Although cocaine is widely used in the United States, cocaine-associated TMA is only rarely reported. Therefore, other factors may predispose cocaine users to the development of TMA. Emerging evidence indicates that cocaine activates complements. Therefore, complement activa- tion may contribute to the development of cocaine-induced TMA. Here, we report a cocaine user who presented with renal failure. Renal biopsy demonstrated TMA. Laboratory tests revealed reduced serum complement C3 and normal complement C4 levels indicative of alternative complement activation. We postulate that complement activation is involved in the pathogenesis of cocaine-induced TMA. Key words: cocaine, complements, endothelial injury, thrombotic microangiopathy Introduction factor. Accumulating evidence indicates that cocaine and its Cocaine use remains a serious public health concern. Although adulterant levamisole may also activate complements [2–4]. cocaine can adversely affect the function of almost every organ Increased complement activity may cause endothelial injury system, the effects of cocaine on the vasculature including and thrombotic microangiopathy (TMA) [5, 6]. those of the kidney, the coagulation system and complements Cocaine use may cause kidney injury secondary to ischemia, are of particular interest to this report [1]. Cocaine causes endo- infarction, rhabdomyolysis, malignant hypertension and TMA. thelial dysfunction characterized by increased endothelin-1 Although cocaine is in widespread use in the United States, (vasoconstrictor) and reduced nitric oxide (vasodilator) release, cocaine-induced TMA is only rarely observed [7–9]. Therefore, thereby promoting vasoconstriction. Cocaine stimulates plate- other factors such as increased complement activity may pre- let activation and aggregation. It further promotes coagulation dispose cocaine users to TMA. Here, we report a middle-aged by increasing the activity of plasminogen activator inhibitor cocaine user who developed TMA accompanied by complement and raising the plasma levels of fibrinogen and von Willebrand abnormalities suggestive of alternative complement activation. Received: August 21, 2016. Editorial decision: May 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Complements in cocaine-induced TMA | 27 We postulate that complement activation is involved in the In all, 11 glomeruli appeared bloodless and demonstrated tuft pathogenesis of cocaine-induced TMA. wrinkling as well as focal and segmental sclerosis. There were severe (80%) interstitial fibrosis and tubular atrophy. There was severe diffuse acute tubular epithelial cell injury. Arteries dem- onstrated moderate arteriosclerosis with foci of superimposed Case presentation edematous intimal expansion resulting in luminal narrowing or A 54-year-old man with a history of polysubstance abuse pre- occlusion (Figure 1A and B). Arterioles showed hyperplastic sented with altered mental status. His past medical history was arteriolosclerosis (Figure 1C). Direct immunofluorescence notable for treatment-naı¨ve hepatitis C infection. Family history microscopy showed no immunoreactants. Ultrastructural was notable for a sister who was diagnosed with renal failure of examination of glomeruli revealed subendothelial widening by obscure etiology requiring dialysis at the age of 45 years. On finely granular and fibrillar material. The hospital course was examination, the patient was found to be afebrile, drowsy and notable for lack of renal recovery and uremia resulting in initia- hypertensive (172/110 mmHg). Jugular veins were distended. tion of hemodialysis. Considering the patient’s psychosocial There were crackles at the lung bases. Blood tests revealed crea- status and the severity of renal fibrosis, eculizumab therapy tinine 16.0 mg/dL, blood urea nitrogen 99 mg/dL, hemoglobin was not considered. The patient was discharged from the hospi- 11.3 g/dL, platelets 222 000/mm , LDH 907 (84–246 IU/L) and hap- tal to receive hemodialysis in a dialysis center in the toglobin 171 (30–200 mg/dL). Urinalysis showed proteinuria. A community. blood film revealed rare schistocytes. Random urine protein-to- creatinine ratio was 1.9. Urine toxicology revealed cocaine and its metabolites. Routine blood and urine cultures showed no Discussion growth. Serologic tests showed reduced complement C3 level of 71 (90–180 mg/dL) and normal C4 level of 32 (10–40 mg/dL). C3 Here, we report a cocaine user who developed TMA. TMA is a hypocomplementemia persisted throughout hospitalization. rare complication of cocaine use. Gu and Herrera observed his- There were no antibodies against HIV 1/2. Ultrasonography topathological features of TMA in 0.9% of 2750 kidney biopsies showed echogenic kidneys measuring 9.8 cm (right) and 10.3 cm [7]. They noted TMA associated with cocaine use and severe (left). A renal biopsy was performed 9 days following admission. hypertension in only 2 (0.07%) biopsies. The authors argued that It contained 62 glomeruli, 51 of which showed global sclerosis. the presence of severe hypertension alone does not appear to Fig. 1. Vascular histopathology. (A) An artery in the kidney showing luminal occlusion secondary to edematous intimal expansion (arrow) (hematoxylin and eosin stain). (B) Same artery as (A), demonstrating the absence of elastic fibers in the expanded intima (arrow) (Verhoeff’s Van Gieson elastin stain). (C) An arteriole demon- strating onion skin-like smooth muscle cell hyperplasia (hyperplastic arteriolopathy) (arrow) (periodic acid–Schiff stain). Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018 28 | A. Dejman et al. be sufficient for the development of TMA associated with infection as the cause of alternative complement activation in cocaine use. Similar to our case, neither case demonstrated our case. In conclusion, we argue that alternative complement marked anemia or absolute thrombocytopenia. Volcy et al. activation induced by cocaine and its adulterant levamisole reported a 38-year-old woman who presented with renal failure can cause TMA. along with hematological and histopathological features of TMA following inhalation of crack cocaine [8]. Balaguer et al. Conflict of interest statement reported a 22-year-old woman with a history of hepatitis C infection who developed acute hepatitis and renal failure fol- None declared. lowing ethanol and intravenous cocaine use [9]. They diagnosed TMA based on clinical and hematological findings. References Because the vast majority of cocaine users do not develop TMA, there must be hitherto poorly understood contributing 1. Schwartz BG, Rezkalla S, Kloner RA. Cardiovascular effects factor(s) that are crucial for the development of cocaine- of cocaine. Circulation 2010; 122: 2558–2569 induced TMA. Much is known about the role of complements in 2. Tanhehco EJ, Yasojima K, McGeer PL et al. Acute cocaine the pathogenesis of atypical hemolytic–uremic syndrome exposure up-regulates complement expression in rabbit (aHUS), which is a life-threatening form of TMA [5]. In aHUS, heart. J Pharmacol Exp Ther 2000; 292: 201–208 loss-of-function mutations affecting complement regulatory 3. Magro CM, Wang X. Cocaine-associated retiform purpura: genes lead to increased complement activity and complement- a C5b-9-mediated microangiopathy syndrome associated with mediated endothelial injury. Conditions that further augment enhanced apoptosis and high levels of intercellular adhesion complement activity (complement amplifying conditions) or molecule-1 expression. Am J Dermatopathol 2013; 35: 722–730 disturb endothelial homeostasis may result in severe microvas- 4. Kondo M, Kato H, Masuda M. Levamisole and serum comple- cular injury and thrombosis in genetically susceptible individu- ment. N Engl J Med 1978; 298: 1146 als [10]. Emerging evidence indicates that cocaine and 5. Nayer A, Asif A. Atypical hemolytic-uremic syndrome: levamisole (a cocaine adulterant) activate the complement sys- a clinical review. Am J Ther 2016; 23: e151–e158 tem. Tanhehco et al. showed that cocaine increased the gene 6. Mathew RO, Nayer A, Asif A. The endothelium as the com- expression of several complement components and the protein mon denominator in malignant hypertension and throm- expression of the terminal complement complex C5b-9 in the botic microangiopathy. J Am Soc Hypertens 2016; 10: 352–359 rabbit heart [2]. Magro et al. reported extensive vascular C5b-9 7. Gu X, Herrera GA. Thrombotic microangiopathy in cocaine deposition in cocaine-induced retiform purpura that is charac- abuse-associated malignant hypertension: report of 2 cases terized by skin necrosis secondary to cutaneous TMA [3]. Duran  with review of the literature. Arch Pathol Lab Med 2007; 131: et al. reported a 28-year-old man with complement factor H defi- 1817–1820 ciency who developed TMA (aHUS) triggered by cocaine use [11]. 8. Volcy J, Nzerue CM, Oderinde A et al. Cocaine-induced acute renal Kondo et al. explored the effects of levamisole on complements failure, hemolysis, and thrombocytopenia mimicking thrombotic in human subjects [4]. They demonstrated that levamisole led thrombocytopenic purpura. Am J Kidney Dis 2000; 35: E3 to complement activation via both classical and alternative 9. Balaguer F, Fernandez J, Lozano M et al. Cocaine-induced pathways. Therefore, we speculate that cocaine-induced com- acute hepatitis and thrombotic microangiopathy. JAMA plement activation can lead to microvascular injury and throm- 2005; 293: 797–798 bosis in genetically susceptible individuals. 10. Asif A, Nayer A, Haas CS. Atypical hemolytic uremic syn- Our patient had a history of hepatitis C infection. The drome in the setting of complement-amplifying conditions: serum C3 protein level can be reduced in patients chronically case reports and a review of the evidence for treatment with infected with hepatitis C compared with healthy individuals. eculizumab. J Nephrol. 2017; 30: 347–362 This is in part secondary to hepatitis C-induced suppression of 11. Duran  CE, Blasco M, Maduell F et al. Rescue therapy with ecu- C3 production in hepatocytes [12]. However, several reports lizumab in a transplant recipient with atypical haemolytic- have shown that hepatitis C infection also reduces comple- uraemic syndrome. Clin Kidney J 2012; 5: 28–30 ment C4 expression and serum levels. Therefore, we believe 12. Mazumdar B, Kim H, Meyer K et al. Hepatitis C virus proteins that normal serum C4 levels argue against hepatitis C inhibit C3 complement production. JVirol 2012; 86: 2221–2228 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/26/3926547 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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