Contrast Induced Nephropathy David Knesek Eric Muller Goals

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Contrast Induced Nephropathy

• David Knesek
• Eric Muller

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Goals

• Identify pts at risk for Contrast Induced
  Nephropathy
• Discuss how to decrease the risk for those pts
• Educate all of you, and us

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Overview

• Background
• Definition/history
• Epidemiology
• Risk factors
• Pathophysiology
• Contrasting contrast
• Loyola statistics
• Literature review
• Hydration
• Mucomyst
• Peri-procedural management
• General guidelines

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In the Beginning

• 1930s
• Osborne images the urinary tract with iodinated
  contrast material
• First cases of contrast induced nephropathy seen
  in 1950s with advent of early IV contrast agents
• Significant increase in contrast over the last 30
  years
• Rise of CT, angiogram and special procedures

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Definition of CIN

• Definitions are variable by study but include
• Rise in creatinine _____ mg/dl or ______ rise
  over baseline
• Must occur within 72h of contrast administration
• Must rule out other causes
• Atheroembolic disease, atn, interstitial
  nephritis, pre-renal

.5-1
25-50
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Epidemiology Overview

• Incidence
• CIN 3 cause of ARF (1 surgery, 2 hypotension)
• Overall risk difficult to ascertain
• Highly dependent on risk stratification
• Roughly 2 of all comers now
• 2002-angiogram data
• Circulation 2002 1052259
• 1 million contrasted studies
• 150,000 CIN
• Unknown what contrast was used or baseline risk
  stratification

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Pathophysiology

• Hemodynamic
• Brief Vasodilatation followed by prolonged
  vasoconstriction?Decreased RBF and GFR?Subsequent
  Ischemia in the PCT and thick ascending limb of
  Henle
• Alteration in Nitric Oxide, endothelin, adenosine
• Studies in animals show no current direct
  relations between these mediators and ischemia
• Observed that Ionic Agents and Hyperosmol agents
  increase risk of vasoconstriction
• Hyperosmolar more viscous and increase chance of
  vascular sludging, enhancing tubular interstitial
  pressure, and further reducing medullary flow

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Pathophysiology

• Cytotoxic
• Direct Cytotoxic Effects of Contrast Dye by the
  generation of oxgen free radicals
• Kidney Int 2003
• Contact of CM with tubular cells causes rapid
  loss of cell membrane proteins including Na/K
  ATPase Pump as well as mitochondrial proteins
  such as cytochrome C
• Increase in excretion of lysosomal enzymes and
  small molecular weight proteins ? Nonspecific
  indicators of tubular damage
• Difficult to dissociate true toxicity from
  secondary renal ischemia

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Cool Slide
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Characteristics of CIN

• Creatinine starts to rise within ______ hrs
  post-procedure
• Complete recovery typically in ______ days
• Urine output is _________
• FeNa high or low

12-24
5-7
Normal
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Ruling out other causes

• Atherembolic disease
• Later rise in Cr, may be permanent
• Eosinophils in urine
• FeNa gt1
• Low complement
• ATN-high FeNa, tubular casts, typically another
  precipitating cause, long recovery
• Interstitial Nephritis decreased urine output,
  WBCs, RBCs in UA

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Risk by Renal Function

• Negligible risk with normal renal function
• Kidney Int 1995 47254 and N Engl J Med
  1989320143
• 4-11 risk with moderate renal insufficiency (Cr
  1.5-4 mg/dl)
• Am J Med 1989 86649 and Kidney Int 1992
  411274
• 50 or more if baseline Cr gt 4-5 mg/dl
• AJR Am J Roentgenol 1991 15749 and Am J Med
  1990 89615

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Other Risk Factors

• 40 increase risk with DM
• Severe CAD
• CHF
• CRF
• Intra-aortic balloon pump
• Multiple contrast exposures within 72h
• Multiple myeloma
• Age gt75y
• Hypotension
• Anemia
• Volume of contrast

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Does Creatinine Matter?

• ARF associated with significant increases in
  in-hospital mortality
• In-hospital mortality (22 vs 1.4 without RF)
• 1 and 5y mortality(12 vs 4 and 45 vs 15)
• HD also significantly associated with mortality
• 30 in-hospital mortality
• 80 2-year mortality
• Rev Cardiovasc Med 2003 4Suppl 5S3-9
• Significant increase in length of stay and cost

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Contrast Agents

• 1st Generation agents ionic monomers and highly
  hyperosmolal (1400 to 1800 mosmol/kg)
• 2nd Generation agents nonionic monomers and lower
  osmolality (500-800 mosmol/kg)
• 3rd Generation agents are iso-osmolal
  (290mosmol/kg), non-ionic dimers

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Properties of Contrast

• Osmolality
• 300-1800mosm/L
• Viscosity
• Iso-osmolar viscosity gt low osmolar
• Ionicity
• New dyes are non-ionic
• Repeated administrations
• lt72h
• Route of administration
• Intravenous vs intra-arterial

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Properties of Contrast
Omnipaque
Visipaque
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Loyola Statistics

• Data obtained from CT, cath lab
• Unable to get special procedures
• CT scans-all types
• 27,800/48,500 with contrast
• Loyola radiology dept uses omnipaque (Non-ionic,
  Low-Osmolar)
• Cath lab
• 744 angiograms over previous 12m
• 519 diagnostic, 225 interventional

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Contrast Studies

• High vs low osmolar
• Meta-analysis of 25 RCTs (1993)
• Benefits seen only in subgroup analysis
• Pre-existing renal failure (gfr lt70)
• Intra-arterial injection of contrast
• No benefit seen in pts with normal renal function
• High osmolar dye no longer used

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More Contrast Studies

• Low vs iso-osmolar
• 4 meta-analyses done
• ¾ compared iohexol (LO) and iopamidol (LO) vs
  iodixanol (IO)
• Iohexol found to be inferior
• No difference between other two
• Loyola uses iohexol (omnipaque)

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Summary of iso vs low osmolar studiesNephrology,
Dialysis, Transplant (2005)
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And yet more contrast studies

• ¼ studies showed benefit for iso-osmolar
• Meta-Analysis (2727 pts)of 16 double-blind,
  controlled trials comparing LOCM to Iodixanol
• Significant lower rate of CIN with Iso-Osmolal
• All comers
• 1.4 vs 3.5, plt0.001
• CKD (Cr gt 1.5) in 502 pts
• 2.8 vs 8.4, p0.001
• CKD and DM in 231 pts
• 3.5 vs 15.5, p0.003
• Iso-osmolar group had lower iodine dose

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IV Hydration

• Mainstay of CIN prevention
• Hydration with ½ NS superior to forced diuresis
  with lasix or mannitol
• 0.45 vs 0.9
• 0.9 superior in pts with nl renal function (1
  study)
• If Cr gt1.6, no difference (1 study)
• Inconclusive data regarding bolus hydration vs
  standard infusion

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Got Bicarb?

• Theoretical tubular protective benefit through
  prevention of free radical formation
• Randomized prospective trial of 119 pts with and
  without renal failure
• JAMA 2004
• Administration of NS or Bicarb as a 3ml/kg one
  hour prior to contrast, followed by a 1 ml/kg
  infusion for six hours afterward (baseline Cr
  similar for both groups)
• Overall Incidence of CIN was 7.6 and was lower
  (1 pt vs 8 pts 1.7 vs 13.6) in Bicarb group
• Studied stopped early do to ethical concerns and
  all pts treated with Bicarbonate
• Study underpowered
• Second study showed similar results

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AcetylcysteineRotten or not?

• Acetycysteine is a thiol compound with
  antioxidant and vasodilatory properties
• Extensive 1st pass metobolism, significant
  variability in bioavailability (3-20), near
  completely protein bound
• Possibly alters the kidneys handling of Cr
• Cr shown to decrease after administration
• Study showing that cystatin C remains constant
• Small molecule freely filtered
• Produced by all nucleated levels
• No adjustments for age, wt, ht, sex, muscle mass

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Mucomyst Studies

• 12 meta-analyses, 29 RCTs
• 7 favor mucomyst, 5 equivocal
• Publication bias
• Negative studies more likely just abstracts
• Both groups had significant heterogeneity in
  their RCTs
• Some evidence that IV mucomyst beneficial before
  urgent procedure
• Some evidence that increasing dose to 1200mg is
  beneficial

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Theophylline

• Increases cAMP, adenosine antagonist
• Can give 200mg IV 30m prior to emergent
  procedures
• Use caution due to risk of arrythmia and
  tachycardia
• Small ICU study (150 pts) found this to be
  superior to mucomyst
• Multiple other studies with equivocal results

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Random Stuff

• Prophylactic hemodialysis
• Not recommended
• Acetazolamide
• Small study at Rush showed benefit over bicarb in
  pediatric population
• Melatonin
• Contrast filter
• JACC 2006
• 8 pigs had coronary sinus filter placed via
  femoral vein
• 49 of contrast removed
• All pts did well

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Mehran et al. StudyRisk StratificationVan
Praet, JACC 2004

• Objective risk score of CIN after Percutaneous
  Coronary Intervention
• Methods
• Prospective, randomized study of 8357 pts
• 5,571 used for development dataset
• 2,786 used for the validation dataset
• Multivariate logistic regression used to identify
  independent predictors of CIN with a p value
  lt.0001 in development set
• Based on odds ratio 8 variables were assigned a
  weighted integer the sum of the integers was a
  total risk score for each pt

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Odds RatioMultivariate Predictors CIN after PCI
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Mehran risk scoring and CIN risk
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Guidelines

• Low risk
• Drink 500ml before and 2500ml/24h after procedure
• If npo, 1ml/kg/h (100cc/h) 4h prior and 24h after
• Medium risk
• If possible, delay procedure to correct
  hemodynamic status
• 0.9 saline 1ml/kg/h 12h before and 12h after
• If chance of volume overload, use 0.45
• If unable to get 6h of hydration, use high volume
  protocol 3ml/kg/h x1h, then 1ml/kg/h x12h
• Keep dye load to minimum and use low or
  iso-osmolar
• Give mucomyst, 1200mg po x4, 2 prior, 2 after
• If emergent, first dose can be IV

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Guidelines contd

• High risk
• Get renal consult
• Consider ICU admission
• Use hydration protocol as above though chance of
  fluid overload in this group is typically high
• Our suggestion-consider bicarb
• Mucomyst or theophylline

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Guidelines

• Specific Recommendations
• Anti-htn
• Cont through procedure
• This includes ace inhibitors
• Diuretics
• Hold 24h prior and 24h after
• Nsaids
• Withdraw prior, restart once confirmed that CIN
  did not occur
• Metformin
• Hold morning of procedure
• Do not restart until renal function verified
• Mannitol is bad
• Follow Cr for 24-48h in med/high risk pts

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Future directions

• Standardize protocols for IVF and other agents
• Standardize definition
• Power for hard end-points of CIN, HD, all-cause
  mortality
• Large RCTs using these standardized protocols
• Loyola specific
• Consider using agent other than iohexol

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Gadolinium
Bonus Slide

• Gadolinium (Gd) non-ionic, low-osmolal (650
  mosmol/kg)
• Excreted exclusively from kidneys
• Half life of 1.3 in healthy individuals
• Half life 34 hours in pts with CRF
• Nephrogenic Systemic Fibrosis
• 215 cases as of Dec 2006
• No cases seen before 1997 suggesting NSF new dz
  probably d/t exposure of CRF pts to new
  medication, infectious agent, or toxin
• Disorder only seen in CRF pts
• Thickening and hardening of skin overlying trunk
  and extremeties and fibrosis of internal organs
  including lungs, myocardium
• Calcification of soft tissue, muscle, myocardium,
  and valves
• Dx by Histology Thickened collagen, prolif of
  fibroblast and elastin, and absence of
  inflammation
• Possible association with Gadolinium

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Gadolinium

• Eur Radiology 2006
• More than 150 pts have developed NSF after
  exposure to Gd based contrast
• 90 had gadolidiamide with certaintly
• No cases of NSF with normal kidney function
• 200 million pts received Gd contrast since early
  80s with 30 million receiving gadolidiamide
• FDA still evaluating correlation between Gd and
  NSF

• Current Recommendations
• No Gd if GFR lt 30 or pts on dialysis
• Avoid use of galodiamide (Omniscan) and use other
  Gd preparation such as Gabobenate Dimeglumine
  (Multihance) if pts must receive gadolinium
  contrast