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Imaging in Acute Kidney Injury, how not to harm patients

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  • 13 cases of NSF from September 2002 through January 2006Copenhagen University HospitalAll 13 had been exposed to gadodiamide a median of 25 days prior to the first symptom (2 to 75 days)
  • One month later report that NFD lesions have miniscule but detectable gadolinium in them at the locations of calcification
  • Prince et al reported on 15 cases of NSF from two institutionsarf defined as creatinine rising 0.5 mg/dl on two meaurements in the week before gad exposure
  • Prince et al reported on 15 cases of NSF from two institutionsarf defined as creatinine rising 0.5 mg/dl on two meaurements in the week before gad exposure

Imaging in Acute Kidney Injury, how not to harm patients Imaging in Acute Kidney Injury, how not to harm patients Presentation Transcript

  • Imaging in acute kidney injury: how to kill as few patients as possible
    Imaging in acute kidney injury:
    Joel Topf, M.D., JACN
    Just another clinical neprhologist
    Detroit, Michigan, USA
    St John Hospital and Medical Center
    http://www.PBfluids.com
  • Anaritide
    Fenoldopam
    High intensity dialysis
    Dopamine
    High dose furosemide
    Allgren et al. N Engl J Med (1997) vol. 336 (12) pp. 828-34
    VA/NIH Acute Renal Failure Trial Network et al. N Engl J Med (2008) vol. 359 7-20
    Tumlin et al. Am J Kidney Dis (2005) vol. 46 (1) pp. 26-34
    ANZICS Clinical Trials Group. Lancet 2000;356:2139-47
    Cantarovich et al. Am J Kidney Dis (2004) vol. 44 (3) pp. 402-9
  • Patients with primary diagnosis of AKI have higher mortality when they are:
    admitted on week-ends
    admitted to smaller hospitals
    James et al. Weekend Hospital Admission, Acute Kidney Injury, and Mortality. Journal of the American Society of Nephrology (2010) vol. 21 (5) pp. 845-851
  • Despite the lack of evidence based success, good care makes a difference
    We just don’t know what that “good care” looks like
  • With out evidence we are left to wander with only our clinical sense to guide us
    Avoid hypotension
    Maintain urine flow
    Avoid renal toxins
    Maintain electrolyte balance
    Maintain fluid balance
  • ICU associated AKI is characterized by a delay between admission and development of acute renal injury
  • In contrast to most cases of community-acquired AKI, nearly all cases of ICU-associated AKI result from more than a single insult
    In the critically ill patient, the first kidney insult is often not predictable.
    For example, in a retrospective study of 5000 ICU patients, 67% of patients had AKI develop, and 45% of AKI occurred after ICU admission.
    It is in these patients that there is a potential role for prevention.
  • 1 day
    4 days
    Hoste et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care (2006) vol. 10 (3) pp. R73
  • Uchino et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA (2005) vol. 294 (7) pp. 813-8
  • This delay in the development of AKI is an opportunity.
    Patients who develop ICU associated AKI may require a second hit.
  • With out evidence we are left to wander with only our clinical sense to guide us
    Avoid hypotension
    Maintain urine flow
    Avoid renal toxins
    Maintain electrolyte balance
    Maintain fluid balance
    • Relate this to imaging
    • Avoid contrast induced renal toxicity
    • Avoid nephrogenic systemic fibrosis
  • Contrast
  • Hydration
    0.9 normal saline
    +/- Isotonic bicarbonate
    Minimize contrast exposure
    Low or isosmolar contrast
    +/- N-Acetylcysteine
  • 2,308 patients randomized to 1,200 mg of N-acetylcysteinex 4 doses
    No improvement in:
    Contrast induced nephropathy
    Change in Cr
    Need for dialysis
    30 day mortality or CV mortality
    Sub group analysis looking at:
    Age
    Creatinine
    Diabetes
    Gender
  • Hydration
    0.9 normal saline
    +/- Isotonic bicarbonate
    Minimize contrast exposure
    Low or isosmolar contrast
    +/- N-Acetylcysteine
    Techniques of particular interest to patients with acute kidney injury
    Dialysis
    Hemofiltration
  • Hemodialysis following contrast
    Moon et al first demonstrated the ability to remove contrast in patients with pre-ESRD CKD by dialysis
    A 6 hour hemodialysis session was able to remove 77% of the contrast load
    Moon et al. Nephron (1995) vol. 70 (4) pp. 430-7
  • First randomized controlled trial
    N=30
    Cr 2.4 ±0.16
    DM 43%
    3 hours of HD started 63±6 min after contrast
    Iopental, a low osmolar, non-ionic contrast
    CIN defined as an increase of creatinine of 0.5 mg/dL at 48 hours
    Lehnert T, Et al Nephro Dial Transplant. 1998 13(2): 358-62.
  • Dialysis accelerated clearance
    At 24 hours
    Dialysis: 89% of contrast was gone
    Control 83% of contrast was gone
    dialysis
  • But didn’t save the kidneys
    dialysis
  • Second RCT, 3 times the size
    113 patients
    Cr 3.5 ± 1 (GFR 21 mL/min)
    33% diabetes
    Hemodialysis started 120 minutes after contrast
    3 hours of HD
    Vogt et al. Am J Med (2001) vol. 111 (9) pp. 692-8
  • Contrast Dose (P=0.007)
    Control: 143 ±115
    Hemodialysis: 210 ±143
    Contrast Nephropathy (P=0.35)
    Control: 9 (16%)
    Hemodialysis 13 (24%)
    Hemodialysis (P=0.12)
    Control: 3 (5%)
    Hemodialysis 8 (15%)
    Solid line: dialysis
    Dotted line: control
  • Moon initiated dialysis 1.8 hours after exposure
    Lehnertinitiated dialysis 1 hour after exposure
    Vogt initiated dialysis 2 hours after exposure
    Could earlier hemodialysis make a difference?
  • No
    7 patients with hemodialysis started 10 minutes prior to left heart cath
    10 patients with IVF in the control group
    No need for further dialysis in either group
    No difference in the average serum Cr at 48 hours and 1 week
    Frank et al. ClinNephrol (2003) vol. 60 (3) pp. 176-82
  • Largest dialysis trial
    424 patients
    3x the size of Vogt
    Cr 1.3-3.5
    CIN defined as Cr rise of 0.5 at 48-72 hours
    Three arms
    Control 6.1%
    Dialysis 15.9%
    NAC 5.3%
    P=0.008
    Cr was not different at 30-60 days
    Reinecke H, Fobker M, Wellmann J, Et al. Clin Res Cardiol. 2007 Mar;96(3):130-9.
  • What about the worst of the worst?
    CKD stage 5 not on dialysis
    Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20
  • Cr > 3.5
    90 patients randomized to dialysis or usual care
    4 hours, no UF
    81±32 min after contrast (45-180)
    24 hour CrCl on 4th day after contrast
    Lehnert
    • No ITT analysis
    • 8 patient not analyzed
    • Insufficient f/u, NSAIDs, 2nd contrast exposure and NAC, off protocol
    Vogt
    Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20
  • Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20
    Cr and CrCl improved at 4 days
  • Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20
    Cr is lower at day 4, peak and D/C
  • 18
    14
    5
    1
    2
    0
    Less temporary and permanent dialysisLess cases of severe CIN
    Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20
  • Conventional Dialysis
    Diffusive Clearance
    Dialysate
  • CVVH
    Convective clearance
    Ultrafilter 3+
    liters/hour
    Replace all ultrafiltratewith sterile fluid at idealplasma concentrations
  • What about hemofiltration
    Marenzi et al.
    Removal
    Dilution
    114 patients (Cr = 3, 30% DM) randomized to
    CVVH
    Began 4-6 hours before contrast, continued for 24 hours
    Hydration
    CIN defined as an Cr increase >25 % from base-line
    Emergency dialysis was protocolized:
    oligouria for more than 48 hours despite use of more than 1 g of IV furosemide
    Marenzi et al. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med (2003) vol. 349 (14) pp. 1333-40
  • Contrast induced nephropathy (P=0.001)
    control: 28 (50%)
    hemofiltration: 3 (5%)
    Emergency HD
    control: 10 (18%)
    hemofiltration: 0
    Hospital mortality (P=0.02)
    control: 8 (14%)
    hemodialysis: 1 (2%)
    1 year mortality (P=0.01)
    control: 17 (30%)
    hemofiltration: 6 (10%)
  • So the hemofiltration group differed from the control group by receiving:
    More IVF
    Removal of contrast
    Anticoagulation
    IV Alkali in the form of replacement fluid
    ICU care
  • Follow up study
    92 patients
    Three protocols
    IVF 12 hours before and after contrast
    CVVH for 18-24 hours after contrast
    CVVH for 6 hours before and 18-24 after contrast
    Designed to isolate contrast removal from fluid administration
    Marenzi G, Lauri G, Campodonico J, et al. Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients. Am J Med 2006;119:155–162.
  • IVF
    CVVH After
    Before and after
  • Pre/Post hemofiltration was 95% protective for contrast nephropathy compared to saline
    Pre/Post hemofiltration was 90% protective for contrast nephropathy compared to post hemofiltration
  • So the pre/post hemofiltration group received
    More IVF
    Removal of contrast
    Anticoagulation
    Alkali exposure
    ICU care
  • summary
  • Hemodialysis is generally considered ineffective at protecting the kidneys from CIN
    Cruz et al. Am J Kidney Dis (2006) vol. 48 (3) pp. 361-71
  • However…
    Data on the weakest kidneys was positive
    Hemofiltration has been effective in two RCTs
  • Nephrogenic systemic fibrosis
    Swollen and thickened skin
    Wood-like texture
    Decreased range of motion
    Presenting over days to weeks
    Broome et al. AJR Am J Roentgenol (2007) vol. 188 (2) pp. 586-92
  • Twenty-four– month mortality was 48% and 20% in patients with and those without cutaneous changes of NSF, respectively
    Todd et al. Arthritis Rheum (2007) vol. 56 (10) pp. 3433-41
  • Novel Disease
    First patients with dermal features suggestive of scleromyxedemawere identified in 1997 (published in 2000)
    Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. The Lancet 2000; 356(9234):1000-1
    1997
    A follow-up article on the same patient series. Characterized the histology and identified it as a novel disease they named NephrogenicFibrosingDermopathy
    • Cowper SE, Su L, Robin H, Bhawan J, LeBoit PE. Amer J Dermatopathol 2001; 23(5): 383-393
    2001
  • 2000-2006No idea of what triggered NSF
    ACEi
    Sevelamer
    Epoetin
    Ischemia
    Clotting abnormalities
    Anti-phospholipid antibodies
    Abnormal Ca-Phos metabolism
    Trauma
    Acidosis
  • 5
    Five patients who received gadodiamide and developed NSF
    4
    Four patients who also received gadodiamide but did not develop NSF
  • 10 months later
  • …we have not observed a single case of NSF among patients who were not exposed to gadodiamide…
  • Boyd et al. Gadolinium deposition in nephrogenicfibrosingdermopathy. Journal of the American Academy of Dermatology (2007) vol. 56 (1) pp. 27-30
  • Gadopentetate (magnevest) introduced
    1988
    Gadodiamide (Omniscan) approved
    1993
    1997
    First case of NSF 1997
    Galan A, Cowper SE, Bucala R: Nephrogenic systemic fibrosis (nephrogenicfibrosingdermopathy). CurrOpinRheumatol 18: 614–617, 2006
    Examined two tissue repositories to find unrecognized cases prior to 1997.
  • Co-factor to trigger NSF?
    ACEi
    Sevelamer
    Epoetin
    Ischemia
    Clotting abnormalities
    Anti-phospholipid antibodies
    Abnormal Ca-Phos metabolism
    Trauma
    Acidosis
  • Risk of NSF following gadolinium
  • Not all gadolinium are equal
    Gadolinium is insoluble in water and highly toxic
    For human use gadolinium needs to be chelated
    All the brands of gadolinium differ in the nature of the chelation molecule
  • Gadodiamide
    K=16.9
    Gadoteridol
    K=23.8
    1,000,000x more free, toxic Gd
  • Gadodiamide
    Gadoteridol
    Mount Elbert 14,440 feet
    Thickness of an iPod, 0.26 inches
    1,000,000x as tall
  • The gadolinium matters
    Estimated doses (millions)*
    Adapted from data presented at Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees
    *2005-2008 IMS National Sales Perspectives™, Year 2005- 2009
    ** post marketing adverse events. FDA Office of Surveillance and Epidemiology
  • 2.4% risk
    3 patients of 87 who received 123 exposures
    Deo A, Fogel M, Cowper SE. Clin J Am Soc Nephrol 2007;2:264–7.
    18% risk
    18/102 patients exposures to gadodiamide exposure
    Rydahl C, Thomsen HS, Marckmann P. Invest Radiol 2008;43:141– 4.
    0% risk
    0 of 141 exposures to gadoteridol (ProHance)
    Reilly RF. Clin J AmSocNephrol 2008;3:747–51.
    30% risk
    16/54. Prospectively examined patients for dermatologic signs of NSF after exposure to gadopentetate
    Todd DJ, Kagan A, Chibnik LB, et al. Arthritis Rheum 2007;56:3433–41.
    8.4% risk
    Patients with a GFR <15 mL/min (not on dialysis) receiving gadolinium developed NSF
    Prince MR, Zhang H, Morris M, et al. Radiology 2008;248:807–16.
    0.05% risk with gadodiamide
    0.002% risk with gadopentetate
    Used all MRI scans as the denominator
    Wertman R, Altun E, Martin DR, et al. Radiology 2008;248:799 – 806
  • NSF in acute renal failure
    The condition occurs in acute renal failure but much of the focus has been on chronic dialysis patients
    Todd DJ, Kagan A, Chibnik LB, et al. Arthritis Rheum 2007;56:3433–41.
  • Perez-Rodriguez looked at 33 cases of biopsy proven NSF from a single center
    7 were AKI (21%)
    5 subsequently recovered renal function,
    That did not lead to improved symptoms
    Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA 2009 Radiology, 250, 371-377
  • 11 of 15 (73%)patients were in acute kidney injury
    Prince et al. Radiology (2008) vol. 248 (3) pp. 807-16
  • 4 of 12 cases (33%) from a single institution were in acute renal failure
    3 of the 4 were due to hepatorenal syndrome
    Broome et al. AJR Am J Roentgenol (2007) vol. 188 (2) pp. 586-92
  • Avoiding NSF
    Because there is no effective therapy for NSF, avoidance of exposure is the best option
    View the unenhanced images to verify the need for gadolinium enhancement
    Minimize dose
    avoid MR angiogram
    Low risk gadolinium- containing contrast agent
  • Gadolinium contrast agents are rapidly cleared
    half life of 1.3 hours in healthy volunteers.
    In CKD the half-life can be extended from 30 to 120 hours.
    70 dialysis patients, 4 hours hemodialysis session
    Okada S, Katagiri K, Et al. ActaRadiol 2001; 42: 339-341.
  • 14 of 15 patients had either no dialysis or delayed dialysis
    Prince et al. Radiology (2008) vol. 248 (3) pp. 807-16
  • 33 cases of NSF
    8 not on dialysis
    5 on peritoneal dialysis
    20 on hemodialysis
    7 received HD on the day of exposure
    13 unable to determine the timing of dialysis in regards to gadolinium exposure
    Perez-Rodriguez et al. Radiology (2009) vol. 250 (2) pp. 371-7
  • 3 of 12 cases (33%) received dialysis on the day of exposure and then daily for three days
    And they developed NSF
    Broome et al. AJR Am J Roentgenol (2007) vol. 188 (2) pp. 586-92
  • Recovery of renal function
    Some authors report improvement in symptoms with improvement in renal function
    Cowper. Am J Kidney Dis (2005) vol. 46 (4) pp. 763-5
    Perez-Rodriguez reported on 5 cases of NSF in association with renal failure with a liver transplant.
    Every patient recovered renal function within 6 weeks, none had improvement in NSF
    One patient’s kidney function recovered days prior to developing skin changes
    Perez-Rodriguez et al. Radiology (2009) vol. 250 (2) pp. 371-7
  • Summary
    Nephrogenic Systemic Fibrosis is a devastating complication
    The risk, in patients with decreased renal function and inflammatory insults, likely runs from 5 to 30% following a single Gd exposure
    Though dialysis if suggested as a way to reduce harm, there are case reports of patients who have developed NSF despite this
  • Summary
    Avoid gadolinium
    Use safer formulations of gadolinium, Gadovist, ProHance if necessary
  • Does anybody have any questions?
    The big finish