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How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

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Page 1: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

How Does Cocaine Abuse Cause

Renal Failure?

David Shure

May 26, 2009

Page 2: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Differential Diagnosis

• Cocaine induced malignant HTN/ TMA

• ATN

• GN

• Worsening Creat 4/10 = rapid lowering BP

Page 3: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Background

• Est: 23 mil Americans have used cocaine• Subst abuse cost to US economy: ~144 bil/

year• Cocaine-related hospitalizations ~ 80mil/year• Well estab assoc with CVD, accelerated

ASHD, CVA, accident-related deaths• connection with renal failure not well

established other than 2/2 rhabdomyolysis

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Metabolism

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Cocaine: Potent Vasoconstrictor

• Inhibits presynaptic nerve terminal catechol reuptake

• Blocks reuptake norepinephrine

• Stimulates release norepi/ epi from adrenal medulla

• Incr Ca influx in vascular smooth muscle

Page 8: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Other Vasoconstrictive Pathways

• ET-1

• RAAS

Page 9: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Endothelins• ET-1 = major ET isoform involved in renal

dysfunction• High density ET-1 receptors in vascular smoth

muscle of all renal vessels• Activation causes decr renal blood flow and GFR

,constricts both afferent and efferent arterioles, arcuate and interlobular arterioles.

• Peptide found upregulated in pregnant pt’s with cocaine use

• Levels of ET-1 in cocaine similar to preeclampsia, however in cocaine using pt’s, levels persist well past post-partum period attributed to cocaine metabolites

Page 10: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

RAAS• Hendricks et al: Cocaine-stimulated Endothelin-1

release is decreased by ACE-I in cultured endothelial cells. Cardivasc Res, 1996

• Endothelial cells produce endogenous ACE, suggests effects of ACE-I on BP and CV due to local effects on endothelial cells.

• Captopril downregulates ET-1 release in cultured endothelial cells.

• Captopril + diazepam led to incr survival time in rats exposed to lethal levels of cocaine.

• Activation of RAAS and AGII by cocaine may lead to renal fibrosis from stim TGF-b

Page 11: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Cocaine Effects on Renal matrix and Oxidative Stress

• FSGS/ DM Nephrop: accumulation of matrix w/mesangial expansion may precede clinical dz

• Cocaine may enhance renal cortical mRNA expression of tissue inhibitors of metallopreoteinase-2, leading to incr matrix accumulation

• Cocaine also incr oxidative stress in kidney. Cultured kidney cells exposed to cocaine found to reduce the level of IC glutathione.

Page 12: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009
Page 13: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

TMA in Cocaine Abuse - Assoc Malignant HTN

2 Cases• Xin et al: Arch Pathol Lab Med; Dec

2007 Louisiana State Univ

• Cocaine toxicity not only induces VC but also known to precipitate diffuse endothelial injury as a result of malignant htn leading to impaired renal blood flow and ARF

Page 14: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Case 1• 48 M s/p trauma/bleeding to left ear, denies drugs

but cocaine +; No other sxs• BP 210/110• BUN/Creat: 90/11• Plt/ LDH: WNL• Schisto: <1%• Hx HTN x1 yr• Last serum creat one yr ago: 1.2mg/dl• HCV/HBV/ANACA/ANA/RPR/RF Neg• 24 hr Ur prot: 2 g• One year later creat 3-4 mg/dl

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Case 2

• 39 M, 2d HA +blurred vision; no PMH

• BP 200/110; denied drugs, cocaine +

• Creat 9mg/dl, dialyzed for ARF

• Renal bx then lost to f/u

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Comments: Endothielial damage and PLT activation

• Renal bx findings typical for TMA • Most cocaine-intoxicated pts have short-lasting

HTN with no significant renal impairment, HTN alone not sufficient to cause TMA

• ET injury inducing vasculopathy • Platelet activation and thrombus formation occur

2/2 cocaine induced MHTN; ADP plat aggregation and TPA inhibitor is increased

• Other factors: chronic HTN, arteriosclerosis, low cholinesterase activity may be involved

Page 20: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Assoc Bet TMA and Reduced ADAMTS13 Activity in Malignant HTN

• Bert-Jan et al: Hypertension Nov 2007• Premise: TMA seen in MHTN is similar to that of

TTP, which is assoc deficiency ADAMTS13• ADAMTS13: A VWF cleaving protease, cleaves

large prothrombogenic multimers • Deficiency ADAMTS13 leaves large

prothrombogenic multimers (UL-VWF) in circulation resulting low plt, IV hemolysis, and ischemic microvascular complications.

• Hypothesis: ADAMTS13 is deficient in MHTN and severity of TMA is assoc w/decr ADAMTS13 activity.

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TMA

• Characterized by:– Thrombosis of small vessels– IV hemolysis with fragmentated RBCs

(schistocytes)– Elevated LDH– Platelet Consumption

Page 26: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Pathogenesis Proposed

1. A 2/2 deficiency of ADAMTS13 seen in situations where high levels circulating VWF 2/2 endothelial damage. Suggests that in state of marked endothelial damage, ie MHTN, deficiency ADAMTS13 activity may devlp aaro binding to the A2 domain of VWF molecule.

2. High fluid shear rates may result in conformational changes of VWF and promote binding of ADAMTS13, reducing its activity.

3. Degree of EC free Hb 2/2 destruction RBCs is shown to inhibit ADAMTS13 in vitro and may lead to 2/2 deficiency in ADAMTS13.

Page 27: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

Design

• 20 pts with MHTN, 20 severe HTN, 20 controls

• Investigated VWF, active VWF, free Hb to explore predictors of ADAMTS13 activity

• Primary outcome: difference in ADAMTS13 activity bet BP grps

• 2nd outcome: assoc bet ADAMTS13 and TMA severity (LDH levels, plt count, schistocytes).

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Findings• ADAMTS13 activity decr in pts with MHTN

and is assoc with severity of TMA, likely bc of release of VWF after endothelial stimulation.

• A severe deficiency of ADAMTS13 as in TTP was not demonstrated, so measurement of ADAMTS13 may help to discriminate between TTP and MHTN.

• 2 Pts with severe HTN with no retinopathy had evidence of TMA suggests that a retinal exam is not sufficient to discriminate those with vs without TMA.

Page 33: How Does Cocaine Abuse Cause Renal Failure? David Shure May 26, 2009

VWF and ADAMTS13• Lower ADAMTS13 activity may lead to expression

of large prothrombogenic VWF multimers, stimulating platelet binding, thrombus formation and development of tissue ischemia and necrosis.

• ADAMTS13 was negatively correlated w/creat, may support concept that even small deficiencies of ADAMTS13 may be relevant in conditions of marked endothelial activation. And may suggest that rx directed at incr ADAMTS13 activity may be beneficial.