imaging in acute kidney injury, how not to harm patients

Imaging in acute kidney injury: how to kill as few patients as possibleImaging in acute kidney injury:

Joel Topf, M.D., JACNJust another clinical neprhologistDetroit, Michigan, USASt John Hospital and Medical Centerhttp://www.PBfluids.com

Dopamine

ANZICS Clinical Trials Group. Lancet 2000;356:2139-47

Fenoldopam

Tumlin et al. Am J Kidney Dis (2005) vol. 46 (1) pp. 26-34

Anaritide

Allgren et al. N Engl J Med (1997) vol. 336 (12) pp. 828-34

High dose furosemide

Cantarovich et al. Am J Kidney Dis (2004) vol. 44 (3) pp. 402-9

High intensity dialysis

VA/NIH Acute Renal Failure Trial Network et al. N Engl J Med (2008) vol. 359 7-20

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

We just don’t know what that “good care” looks like

Despite the lack

of evidence based success, good care makes a difference

• 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

• 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

Contrast

Hydration0.9 normal saline+/- Isotonic bicarbonate

Minimize contrast exposureLow or isosmolar contrast+/- N-Acetylcysteine

• 2,308 patients randomized to 1,200 mg of N-acetylcysteine x 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

Hydration0.9 normal saline+/- Isotonic bicarbonate

Minimize contrast exposureLow or isosmolar contrast+/- N-Acetylcysteine

Techniques of particular interest to patients with acute kidney injury

DialysisHemofiltration

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

Cr (mg/dL) DiabetesContrast

volume (mL)

4.5 DM 470

3.5 DM 980

3.2 177

4.1 377

2.4 259

5.7 313

7.5 97

6.1 DM 176

3.7 DM 227

4.5 377

3.0 476

5.7 DM 264

5.8 237

4.6 38% 340

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

dialysis

• At 24 hours– Dialysis: 89% of contrast was gone– Control 83% of contrast was gone

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

Solid line: dialysisDotted line: control

Contrast Dose (P=0.007)Control: 143 ±115Hemodialysis: 210 ±143

Contrast Nephropathy (P=0.35)Control: 9 (16%)Hemodialysis 13 (24%)

Hemodialysis (P=0.12)Control: 3 (5%)Hemodialysis 8 (15%)

Moon initiated dialysis 1.8 hours after exposureLehnert initiated dialysis 1 hour after exposureVogt initiated dialysis 2 hours after exposure

Could earlier hemodialysis make a difference?

7 patients with hemodialysis started 10 minutes prior to left heart cath10 patients with IVF in the control groupNo need for further dialysis in either groupNo difference in the average serum Cr at 48 hours and 1 week

Frank et al. Clin Nephrol (2003) vol. 60 (3) pp. 176-82

No

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

Lehnert

Vogt

• 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

Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20

• No ITT analysis – 8 patient not analyzed– Insufficient f/u, NSAIDs,

2nd contrast exposure and NAC, off protocol

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

1

14

05

2

18

Less temporary and permanent dialysisLess cases of severe CIN

Lee et al. J Am Col Cardiol (2007) vol. 50 (11) pp. 1015-20

Dialysate

Conventional DialysisDiffusive Clearance

Ultrafilter 3+ liters/hour

Replace all ultrafiltratewith sterile fluid at idealplasma concentrations

CVVHConvective clearance

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 HDcontrol: 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.

Contrast nephropathy

Emergent dialysis

Hospital mortality

IVF alone 12/30 (40%) 9/30 (30%) 6/30 (20%)

CVVH after 8/31 (26%) 3/31 (10%) 3/31 (10%)

CVVH before and after 1/31 (3%) 0/31 (0%) 0/31 (0%)

Between group analysis P=0.0013 P=0.002 P=0.03

Before and after

CVVH After

IVF

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

• Swollen and thickened skin•Wood-like texture• Decreased range of motion• Presenting over days to weeks

Nephrogenic systemic fibrosis

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 scleromyxedema were identified in 1997 (published in 2000)– Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta

S, LeBoit PE. The Lancet 2000; 356(9234):1000-11997

2001

A follow-up article on the same patient series. Characterized the histology and identified it as a novel disease they named Nephrogenic Fibrosing Dermopathy– Cowper SE, Su L, Robin H, Bhawan J, LeBoit PE. Amer J

Dermatopathol 2001; 23(5): 383-393

2000-2006No idea of what triggered NSF• ACEi• Sevelamer• Epoetin• Ischemia• Clotting

abnormalities–Anti-phospholipid

antibodies

• Abnormal Ca-Phos metabolism

• Trauma• Acidosis

5Five patients who received gadodiamide and developed NSF

4Four 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 nephrogenic fibrosing dermopathy. 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 1997Galan A, Cowper SE, Bucala R: Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol 18: 614–617, 2006Examined 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

Brand name genericClass of chelation

agentK (log dissociation

constant)

Optimark GadoversetamideLinear, non-ionic

16.8Omniscan Gadodiamide 16.9Vasovist Gadofosveset

Linear, ionic

22.1Magnesvist Gadopentetate 22.5Multihance Gadobenate 22.6Eovist Gadoxetate 23.5Gadovist Gadobutrol 21.8Prohance Gadoteridol Cyclic, ionic 23.8

GadodiamideK=16.9

GadoteridolK=23.8

1,000,000x more free, toxic Gd

Gadodiamide Gadoteridol

1,000,000x as tall

Mount Elbert 14,440 feet Thickness of an iPod, 0.26 inches

13

23

4.72.6

2.2OmniscanMagnevistOptimarkMultihanceProhance

Adapted from data presented at Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety

and Risk Management Advisory Committees

Estimated doses (millions)*

The gadolinium matters

*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 AmSoc Nephrol

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

Prince et al. Radiology (2008) vol. 248 (3) pp. 807-16

11 of 15 (73%)patients were

in acute kidney injury

• 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

Brand name genericClass of chelation

agentK (log dissociation

constant)

Optimark GadoversetamideLinear, non-ionic

16.8Omniscan Gadodiamide 16.9Vasovist Gadofosveset

Linear, ionic

22.1Magnesvist Gadopentetate 22.5Multihance Gadobenate 22.6Eovist Gadoxetate 23.5Gadovist Gadobutrol 21.8Prohance Gadoteridol Cyclic, ionic 23.8

• 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. Acta Radiol 2001; 42: 339-341.

Prince et al. Radiology (2008) vol. 248 (3) pp. 807-16

14 of 15 patients had either no dialysis or

delayed dialysis

• 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