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1. CONTRAST-INDUCED NEPHROPATHY
(CIN)
PHUNG HUY HOANG, MD
Resident in Internal Medicine
Pham Ngoc Thach University of Medicine
September, 2018

2. OUTLINES
• Overview
• Staging
• Contrast medium
• Pathophysiology
• Characteristics
• Differentiation
• Risk factors
• Prevention
• Arterial vs Venous

3. OVERVIEW
• Iodinated CI-AKI = a 0.3 (mg/dL) or greater rise in serum creatinine from baseline within
48 hours of intravascular administration (Acute Kidney Injury Network)
• Define and stage AKI after administration of intravascular contrast media as per
Recommendations (KDIGO)
• 3rd most common (10%) cause of hospital-acquired AKI
• 3-7% in patients without any risk factors
• 25-50% in patients with moderate to advanced CKD
• International Society of Nephrology (2012), Kidney International Supplements, 2 (1), pp. 124-38
• Sharfuddin A. A., Weisbord S. D., Palevsky P. M., et al. (2016), Brenner & Rector’s The Kidney, Karl Skorecki, Maarten W. Taal, Glenn M. Chertow, Editors, Elsevier, pp. 958-1011
• Masud T., McClellan W. M. (2011), Hurst's The Heart, Valentin Fuster, Richard A. Walsh, Robert A. Harrington, Editors, McGraw Hill, pp. 2162-2175
• Steddon S., Ashman N., Chesser A., et al. (2014), Oxford Handbook of Nephrology and Hypertension, Oxford University Press pp. 88-191

4. CRITERIA
SCr
Urine output
↑ by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 hours
↑ to ≥ 1.5 times baseline, known or presumed to have occurred within the
prior 7 days
OLIGURIA (≤ 0.5 ml/kg/h for 6 hours)
1
2
3
International Society of Nephrology (2012), Kidney International Supplements, 2 (1), pp. 124-38

5. STAGING
International Society of Nephrology (2012), Kidney International Supplements, 2 (1), pp. 124-38

6. CONTRAST MEDIUM (CM)
RCM
Ionic
Monometric
Hyperosmolar
> 1400 mOsm/kg
Diatrizoate,
Iothalamate, Metrizoate
Dimetric
Low-osmolar
600 mOsm/kg
Ioxaglate
Non-ionic
Monometric
Low-osmolar
500-850 mOsm/kg
Iohexol, Iopamidol,
Ioversol, Iopromide,
Ioxilan
Dimetric
Iso-osmolar
290 mOsm/kg
Iodixanol
√

7. PATHPHYSIOLOGY
1. Direct cellular toxicity of iodinated contrast material to nephrons (esp tubular cells) ~
ionicity and osmolality, transient tubule obstruction
2. Altered microcirculation  Intrarenal vasoconstriction of vasa recta
o RM mediates vasoconstriction  affects renal parenchymal oxygenation (esp outer medulla)
o Hyperosmolar RM  enhance solute delivery to distal nephron  increased oxygen
consumption by enhaced tubular sodium reabsorption
o Increase blood viscosity  affect flow in medullary microcirculation
3. Renal endothelial dysfunction
NO synthase, NO concentration, endothelin, adenosine, prostaglandins, vasopressin
4. Microshowers of atheroemboli to kidneys (due to catheter and wire): aortic approach
• Waikar S. S., Bonventre J. V. (2016), Harrison's Principles of Internal Medicine, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Editors, McGraw Hill, pp. 1799-1810
• Sharfuddin A. A., Weisbord S. D., Palevsky P. M., et al. (2016), Brenner & Rector’s The Kidney, Karl Skorecki, Maarten W. Taal, Glenn M. Chertow, Editors, Elsevier, pp. 958-1011
• McCullough P. A. (2018), Braunwald’s Heart Disease - A Textbook Of Cardiovascular Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929

8. Hypoxic and toxic
renal tubular
damage
Renal endothelial
dysfunction
Altered
microcirculation 
vasoconstriction

9. Brown J. R., McCullough P. A. (2014), Textbook of Cardiovascular Intervention, Craig A.
Thompson, Editor, Springer, pp. 53-64

10. Toprak O. (2013), What Should We Know About Prevented, Diagnostic, and Interventional Therapy in
Coronary Artery Disease, Branislav G. Baskot, Editor, InTech, Rijeka, pp. Ch. 16

11. CHARACTERISTICS
• Reversible
• Associated with: longer length of hospital stay, MI, stroke, heart failure, and rehospitalization,…
• Intrinsic tubular injury (ATN)
• However, urinary sodium retention and FENa < 1% (≠ others!)
• Typically oliguria (earliest and often only sign).
• Without CKD: begin 24-48 hrs following exposure ---- peak within 3-5 days ---- resolving within
1 week
• CI-AKI leading to dialysis is rare (0.5-2%, max 3-4%)
• The presence of WBC, WBC cast, dysmorphic RBC, RBC cast  differentiate other causes of
AKI (glomerulus uninjured = intact filtration barrier to blood cells)
• Rudnick M. R. (2016), UpToDate
• Sharfuddin A. A., Weisbord S. D., Palevsky P. M., et al. (2016), Brenner & Rector’s The Kidney, Karl Skorecki, Maarten W. Taal, Glenn M. Chertow, Editors, Elsevier, pp. 958-1011
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930
• Steddon S., Ashman N., Chesser A., et al. (2014), Oxford Handbook of Nephrology and Hypertension, Oxford University Press pp. 88-191

12. Waikar S. S., Bonventre J. V. (2017), Harrison’s Nephrology and Acid-Base Disorders, J. Larry Jameson , Joseph
Loscalzo, Editors, McGraw Hill, pp. 104-122.
“Several causes of ischemia-associated and nephrotoxin-associated AKI
can present with FeNa < 1%, however, including sepsis (ofen early in the
course), rhabdomyolysis, and contrast nephropathy”

13. James M. T., Ghali W. A., Knudtson M. L., et al. (2011), Circulation, 123 (4), pp. 409-16

14. DIFFERENTIATION
• Ischemic ATN
• Acute interstitial nephritis
• Renal atheroemboli
• Cardiorenal syndrome
Urinalysis, ultrasound,…
Not suggest biopsy
• Rudnick M. R. (2016), UpToDate
• Sethi A. N., Kohli J., Patel A. M., et al. (2018), Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel M. Topf, Editors, Elsevier, pp. 94-98

15. RISK FACTORS
• Chonic kidney disease (CKD) (the more severe, the greater risk)
• Diabetes mellitus (DM)
• Hemodynamic instability, intravascular volume depletion
• Use of intra-aortic balloon counterpulsation (IABP)
• Heart failure
• Advanced age
• Anemia
• Procedure-related (Intra-arterial administration > IV, Interventional > diagnostic)
• Clinical issues: hydration and volume expansion; pre-, intra-, postprocedure end-organ rotection with
pharmacotherapy; postprocedural monitoring and expectant care
• Sethi A. N., Kohli J., Patel A. M., et al. (2018), Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel M. Topf, Editors, Elsevier, pp. 94-98
• Waikar S. S., Bonventre J. V. (2016), Harrison's Principles of Internal Medicine, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Editors, McGraw Hill, pp. 1799-1810
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930
• Rudnick M. R. (2018), UpToDate, Paul M Palevsky, Editor

16. Masud T., McClellan W. M. (2011), Hurst's The Heart, Valentin Fuster, Richard A. Walsh, Robert A. Harrington, Editors, McGraw Hill, pp. 2162-2175

17. McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular
Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders,
pp. 1909-1930

19. PREVENTION
• Recognition of risks
• Hydration, volume expansion (iodinated contrast is water soluble)
• Contrast agents choice (type, volume), transradial or femoral approach
• Avoid nephrotoxic drugs (anti-inflammatory agents, aminoglycosides, cyclosporine,…),
metformin
• Discussion (with the patient possibility of dialysis), consultation (with nephrology about
possible preprocedure + postprocedure hemofltration, dialysis management)
• Monitoring
• No established pharmacological treatment alternatives exist for complete prevention or
treatment of CI-AKI3,4
1. Waikar S. S., Bonventre J. V. (2016), Harrison's Principles of Internal Medicine, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Editors, McGraw Hill, pp. 1799-1810
2. McCullough P. A. (2018), Braunwald’s Heart Disease - A Textbook Of Cardiovascular Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929
3. Redfors B., Dordi R., Ben-Yehuda O. (2017), Hurst’s The Heart, Valentin Fuster, et al., Editors, McGraw Hill pp. 2369-2387
4. Rudnick M. R. (2018), UpToDate, Paul M Palevsky, Editor

20. PREVENTION
Hydration (1)
• IV normal saline > isotonic sodium bicarbonate (both are effective, but bicarbonate
provides no additional benefit to saline, needs to be compounded, and is more expensive)
• Target: urine output of 150-200 mL/hr post procedure hydration
• Balance input and output
• Diuretic dependent patients: withholding diuretics  may be sufficient “hydration”
• Mechanism of action: suppressing RAAs,  vasoconstrictive mediators, diluting contrast media, 
transit time of contrast media through kidney,…
• Rudnick M. R. (2018), UpToDate, Paul M Palevsky, Editor
• Sethi A. N., Kohli J., Patel A. M., et al. (2018), Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel M. Topf, Editors, Elsevier, pp. 94-98
• Steddon S., Ashman N., Chesser A., et al. (2014), Oxford Handbook of Nephrology and Hypertension, Oxford University Press pp. 88-191
• McCullough P. A. (2018), Braunwald’s Heart Disease - A Textbook Of Cardiovascular Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929

21. PREVENTION
Hydration (2)
1. Rudnick M. R. (2018), UpToDate, Paul M Palevsky, Editor
2. McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930
3. Brar S. S., Aharonian V., Mansukhani P., et al. (2014), The Lancet, 383 (9931), pp. 1814-1823
Preprocedure Intraprocedure Postprocedure
OUTPATIENTS 3 ml/kg, 1h 1-1.5 ml/kg
Administration of at least 6 mL/kg
postprocedure  1-1.5 ml/kg, 4-6h
INPATIENTS 1ml/kg/h, 6-12h 1 ml/kg/h 1 ml/kg/h, 6-12h
• POSEIDON trial: Left ventricular end-diastolic pressure-guided fluid administration seems to
be safe and effective in preventing contrast-induced acute kidney injury in patients
undergoing cardiac catheterisation3

22. PREVENTION
Contrast agents
• Lowest rates of CIN: nonionic, iso-osmolar iodixanol (e.g Iodixanol)
• Iodixanol > low-osmolar contrast media (LOCM)
• No signifcant difference in rates of CI-AKI in lower-risk patients or intravenously*
• Maximum target volumes:
• Diagnostic < 30 mL
• Intervention < 100 mL
• Staged procedures: >10 days between 1st and 2nd exposures (if CI-AKI occurred with 1st)
• Hilton R. M. (2014), Practical Nephrology, Mark Harber, Editor, Springer, pp. 47-62.
• Steddon S., Ashman N., Chesser A., et al. (2014), Oxford Handbook of Nephrology and Hypertension, Oxford University Press pp. 88-191
• Masud T., McClellan W. M. (2011), Hurst's The Heart, Valentin Fuster, Richard A. Walsh, Robert A. Harrington, Editors, McGraw Hill, pp. 2162-2175
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930
• (*) McCullough P. A., Brown J. R. (2011), Cardiorenal Medicine, 1 (4), pp. 220-234

23. PREVENTION
Gadolinium??
• Cause nephrogenic systemic fbrosis (NSF) in patients on dialysis or with severe
impairment of kidney function  can be debilitating and fatal  cannot be recommended
for the reduction of CIN risk/ESRD!
• Macrocyclic ionic chelate-based gadolinium rather than linear nonionic type
• Lowest dosage possible, avoiding repeated exposures
• Consider hemodialysis after gadolinium administration
• No cases with stage 1 to 3 CKD, only a few cases with CKD 4
• Sethi A. N., Kohli J., Patel A. M., et al. (2018), Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel M. Topf, Editors, Elsevier, pp. 94-98
• Waikar S. S., Bonventre J. V. (2017), Harrison’s Nephrology and Acid-Base Disorders, J. Larry Jameson , Joseph Loscalzo, Editors, McGraw Hill, pp. 104-122.

24. PREVENTION
N-Acetylcysteine (1)
• Randomized trial showed no differences
• Despite conflict data  still recommend NAC
• NAC 1200 mg, orally, twice, before and the day of procedure (rather than 600mg)
• Suggest NOT using IV NAC (lack of convincing evidence of benefit and potential risk of
anaphylactoid reactions)
• Hypothesis: enhanced NO-dependent vasodilation + medullary oxygenation + scavenging of free
radicals,  intracellular glutathione levels  antioxidative properties
• Sethi A. N., Kohli J., Patel A. M., et al. (2018), Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel M. Topf, Editors, Elsevier, pp. 94-98
• Rudnick M. R. (2016), UpToDate
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930

25. PREVENTION
N-Acetylcysteine (2)
• No differences in rates of CI-AKI, ESRD, or other outcomes (death, need for dialysis, or
decline in kidney function)1,2
• Neither NAC nor any other drug is approved for the prevention of CI-AKI, either orally or
intravenously3,4
1. ACT. Investigators (2011), Circulation, 124 (11), pp. 1250-9
2. Weisbord S. D., Gallagher M., Jneid H., et al. (2018), New England Journal of Medicine, 378 (7), pp. 603-614.
3. Rudnick M. R. (2018), UpToDate, Paul M Palevsky, Editor
4. McCullough P. A. (2018), Braunwald’s Heart Disease - A Textbook Of Cardiovascular Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929

26. PREVENTION
Monitoring
• Urine output, esp high-risk patients
• Serum creatinine 24 -48 hrs after procedure
• In high-risk patients: up to more than 72 hrs monitored.
• Holding metformin 48 hrs before and after procedure.
• Steddon S., Ashman N., Chesser A., et al. (2014), Oxford Handbook of Nephrology and Hypertension, Oxford University Press pp. 88-191
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930

27. • Loop diuretics or mannitol can worsen
CI-AKI (if volume replacement
inadequate)
• Dopamine or fenoldopam not provide
protection
• Masud T., McClellan W. M. (2011), Hurst's The Heart, Valentin Fuster, Richard A. Walsh, Robert A. Harrington, Editors, McGraw Hill, pp. 2162-2175
• McCullough P. A. (2015), Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp.
1909-1930

28. McCullough P. A. (2018), Braunwald’s Heart Disease - A Textbook Of Cardiovascular
Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929

29. Intra-Arterial Versus Intravenous
Contrast Media Administration
Incidence of AKI is substantially higher following catheter-based procedures with intra-
arterial CM administration compared to imaging studies with intravenous CM administration
• tend to have more advanced vascular disease than those receiving only intravenous CM  higher
risk of AKI
• invasive nature of catheter angiography  cholesterol crystals, aortic plaque fragments, thrombi 
physically dislodged  microembolization of the renal parenchyma
• transient hypotension or reduced cardiac output leading to postinterventional AKI (may be
misinterpreted as CIN)
• higher peak iodine concentration in the renal vasculature
Wichmann J. L., Katzberg R. W., Litwin S. E. (2015), Circulation, 132, pp. 1931-1936.

31. REFERENCES (1)
1. ACT. Investigators (2011), "Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular
angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT)", Circulation, 124 (11), pp. 1250-
9.
2. Brar S. S., Aharonian V., Mansukhani P., et al. (2014), "Haemodynamic-guided fluid administration for the prevention of contrast-induced acute
kidney injury: the POSEIDON randomised controlled trial", The Lancet, 383 (9931), pp. 1814-1823.
3. Brown J. R., McCullough P. A. (2014), "Contrast Nephropathy and Kidney Injury", Textbook of Cardiovascular Intervention, Craig A. Thompson,
Editor, Springer, pp. 53-64.
4. Hilton R. M. (2014), "Acute Kidney Injury: Epidemiology and Assessment", Practical Nephrology, Mark Harber, Editor, Springer, pp. 47-62.
5. James M. T., Ghali W. A., Knudtson M. L., et al. (2011), "Associations between acute kidney injury and cardiovascular and renal outcomes after
coronary angiography", Circulation, 123 (4), pp. 409-16.
6. John A Kellum N. L. (March 2012), "KDIGO Clinical Practice Guideline for Acute Kidney Injury", Kidney International Supplements, 2 (1).
7. Khwaja A. (2012), "KDIGO clinical practice guidelines for acute kidney injury", Nephron Clin Pract, 120 (4), pp. c179-84.
8. Masud T., McClellan W. M. (2011), "The Heart and Kidney Disease", Hurst's The Heart, Valentin Fuster, Richard A. Walsh, Robert A. Harrington,
Editors, McGraw Hill, pp. 2162-2175.
9. McCullough P. A. (2018), "Interface Between Renal Disease and Cardiovascular Illness", Braunwald’s Heart Disease - A Textbook Of
Cardiovascular Medicine, Douglas P. Zipes, et al., Editors, Elsevier, pp. 1910-1929.
10. McCullough P. A. (2015), "Interface Between Renal Disease and Cardiovascular Illness", Braunwald's Heart Disease: A Textbook of
Cardiovascular Medicine, Douglas L. Mann, Robert O. Bonow, Douglas P. Zipes, Editors, Elsevier Saunders, pp. 1909-1930.
11. McCullough P. A., Brown J. R. (2011), "Effects of Intra-Arterial and Intravenous Iso-Osmolar Contrast Medium (Iodixanol) on the Risk of Contrast-
Induced Acute Kidney Injury: A Meta-Analysis", Cardiorenal Medicine, 1 (4), pp. 220-234.
12. Redfors B., Dordi R., Ben-Yehuda O. (2017), "The Kidney In Heart Disease", Hurst’s The Heart, Valentin Fuster, et al., Editors, McGraw Hill pp.
2369-2387.
13. Rudnick M. R. (2018), "Prevention of contrast nephropathy associated with angiography", UpToDate, Paul M Palevsky, Editor.

32. REFERENCES (2)
14. Rudnick M. R. (2016), "Pathogenesis, clinical feature, and diagnosis of contrast-induced nephropathy", UpToDate.
15. Sethi A. N., Kohli J., Patel A. M., et al. (2018), "Contrast-Induced Nephropathy", Nephrology Secrets, Edgar V. Lerma, Matthew A. Sparks, Joel
M. Topf, Editors, Elsevier, pp. 94-98.
16. Sharfuddin A. A., Weisbord S. D., Palevsky P. M., et al. (2016), "Acute Kidney Injury", Brenner & Rector’s The Kidney, Karl Skorecki, Maarten W.
Taal, Glenn M. Chertow, Editors, Elsevier, pp. 958-1011.
17. Steddon S., Ashman N., Chesser A., et al. (2014), "Acute kidney injury (AKI)", Oxford Handbook of Nephrology and Hypertension, Oxford
University Press pp. 88-191.
18. Toprak O. (2013), "Contrast-Induced Nephropathy", What Should We Know About Prevented, Diagnostic, and Interventional Therapy in Coronary
Artery Disease, Branislav G. Baskot, Editor, InTech, Rijeka, pp. Ch. 16.
19. Waikar S. S., Bonventre J. V. (2017), "Acute Kidney Injury", Harrison’s Nephrology and Acid-Base Disorders, J. Larry Jameson , Joseph Loscalzo,
Editors, McGraw Hill, pp. 104-122.
20. Waikar S. S., Bonventre J. V. (2016), "Acute Kidney Injury", Harrison's Principles of Internal Medicine, Dennis L. Kasper, Anthony S. Fauci,
Stephen L. Hauser, Editors, McGraw Hill, pp. 1799-1810.
21. Weisbord S. D., Gallagher M., Jneid H., et al. (2018), "Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine", New
England Journal of Medicine, 378 (7), pp. 603-614.
22. Wichmann J. L., Katzberg R. W., Litwin S. E. (2015), "Contrast-Induced Nephropathy", Circulation, 132, pp. 1931-1936.

33. CONTRAST-INDUCED NEPHROPATHY
(CIN)
PHUNG HUY HOANG, MD
Resident in Internal Medicine
Pham Ngoc Thach University of Medicine
September, 2018