How Does Cocaine Abuse
Cause
Renal Failure?
David Shure
May 26, 2009
Differential Diagnosis
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Cocaine induced malignant HTN/ TMA
ATN
GN
Worsening Creat 4/10 = rapid lowering
BP
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
Other Vasoconstrictive
Pathways
• ET-1
• RAAS
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
RAAS
• Hendricks et al: Cocaine-stimulated Endothelin1 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
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.
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
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
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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
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
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.
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.
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.