Contrast-induced nephropathy explained

Contrast-induced nephropathy
Field:	Nephrology, radiology

Contrast-induced nephropathy (CIN) is a purported form of kidney damage in which there has been recent exposure to medical imaging contrast material without another clear cause for the acute kidney injury.

Despite extensive speculation, the actual occurrence of contrast-induced nephropathy has not been demonstrated in the literature.^[1] Analysis of observational studies has shown that radiocontrast use in CT scanning is not causally related to changes in kidney function.^[2]

Terminology

Given the increasing doubts about the contribution of radiocontrast to acute kidney injury, the American College of Radiology has proposed the name contrast-associated acute kidney injury (CA-AKI) (formerly referred to as post-contrast acute kidney injury; PC-AKI) because it does not imply a causal role, with the name contrast-induced acute kidney injury (CI-AKI) (formerly referred to as contrast-induced nephropathy; CIN) reserved for the rare cases where radiocontrast is likely to be causally related.^[3]

Risk factors

There are multiple risk factors of contrast-induced nephropathy, whereof a 2016 review emphasized chronic kidney disease, diabetes mellitus, high blood pressure, reduced intravascular volume, and old age.

Decreased kidney function

European guidelines classify a pre-existing decreased kidney function to be a risk factor of contrast-induced nephropathy in the following cases:

• Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m² of body surface area before intra-arterial administration with first-pass renal exposure (not passing lungs or peripheral circulation before kidneys), or in the intensive care unit
• eGFR < 30 ml/min/1.73 m2 before intravenous administration or intra-arterial administration with second-pass renal exposure
• Known or suspected acute kidney injury

To calculate estimated GFR (a measure of kidney function) from creatinine, European guidelines use the CKD-EPI formula in adults ≥ 18 years, and the revised Schwartz formula in children. Swedish guidelines recommends no specific formula in children because of lack of evidence, but on the other hand recommends GFR based on cystatin C rather than creatinine in those with abnormal muscle mass, liver failure, or cirrhosis.

Mehran score

The Mehran score is a clinical prediction rule to estimate probability of CIN which includes the following risk factors: systolic blood pressure <80 mm Hg for at least one hour requiring inotropic support, intra-aortic balloon pump, congestive heart failure with New York Heart Association Functional Classification class III or worse, history of pulmonary edema, age >75 years, hematocrit level <39% for men and <35% for women, diabetes mellitus, contrast media volume, decreased kidney function (serum creatinine level >1.5 g/dL or decreased estimated glomerular filtration rate).^{[4] [5]}

Other factors

European guidelines include the following procedure-related risk factors:

• Large doses of contrast given intra-arterially with first-pass renal exposure
• Use of contrast agents with high osmolality (limited use today)
• Multiple contrast injections within 48–72 h. Swedish guidelines also include gadolinium MRI contrast agents in this aspect.

Swedish guidelines list the following additional risk factors:

• Hypoxia
• Cirrhosis
• NSAID or nephrotoxic medication
• Individuals on dialysis with residual renal function of at least 400 ml urine/24h
• Individuals having undergone kidney transplantation

Prevention

The main alternatives in people with a risk of contrast-induced nephropathy are:

• Adjustment of the radiocontrast dose
• Treating or mitigating risk factors
• Using no intravenous contrast for the investigation.
• Switching to another modality such as ultrasonography or MRI.

Dose adjustment

According to European guidelines, the ratio of the contrast dose (in grams of iodine) divided by the absolute estimated glomerular filtration rate (GFR) should be less than 1.1 g/(ml/min) for intra-arterial contrast medium administration with first-pass renal exposure (not passing lungs or peripheral tissue before reaching the kidneys).^[6] Swedish guidelines are more restrictive, recommending a ratio of less than 0.5 g/(ml/min) in patients with risk factors and irrespective of route of administration, and even more caution in first-pass renal exposure.^[6]

Treating or mitigating risk factors

Hydration by drinking or intravenous volume expander, either before or after contrast administration, decreases the risk of contrast-induced nephropathy.^[7] Evidence also supports the use of N-acetylcysteine with intravenous saline among those getting low molecular weight contrast. The use of statins with N-acetylcysteine and intravenous saline is also supported.^[8]

• Oral hydration may be as effective as the intravenous route for volume expansion to prevent contrast-induced nephropathy, according to a review in 2013.^[7]
• Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help^[9] although studies have conflicting results.^[10]
• N-acetylcysteine (NAC) by mouth twice a day, on the day before and of the procedure if creatinine clearance is estimated to be less than 60 mL/min [1.00 mL/s]) may reduce risk. Some authors believe the benefit is not overwhelming.^[11] A systematic review concluded that NAC is "likely to be beneficial" but did not recommend a specific dose.^[12]
• Ascorbic acid may be protective against CIN, according to a systematic review of randomized controlled trials.^[13]
• Matched hydration, meaning infusion of a volume of normal saline equal to the urine output, has been found to reduce kidney injury, dialysis, adverse events and mortality compared to standard therapy.^{[14] [15]}

Diagnosis

CIN is classically defined as a serum creatinine increase of at least 25% and/or an absolute increase in serum creatinine of 0.5 mg/dL^[16] after using iodine contrast agent without another clear cause for acute kidney injury,^[17] but other definitions have also been used.^[2]

The American College of Radiology recommends the usage of the AKIN criteria for the diagnosis of CIN or PC-AKI. The AKIN criteria states that the diagnosis is made if within 48 hours from intravascular contrast medium exposure one of the following occurs:

1. Absolute serum creatinine increase of ≥0.3 mg/dl (>26.4 μmol/L)
2. Relative serum creatinine increase of ≥50 % (≥1.5-fold above baseline)
3. Urine output reduced to ≤0.5 mL/kg/hour for at least 6 hours

Mechanism

The mechanism of contrast-induced nephropathy is not entirely understood, but is thought to include a combination of direct renal tubule damage from the contrast agent and reductions in blood flow to areas of the kidney.^[18] The contrast agent directly damages renal tubule cells by a variety of mechanisms, one proposed mechanism is by causing changes in cell polarity. The sodium potassium pump (also known as the Na+/K+ ATPase) is redistributed from the basal surface to the luminal surface of renal tubule cells. This causes sodium to be transported into the lumen where it is delivered to the distal renal tubule. This sodium load being delivered to the distal renal tubule leads to renal vasoconstriction via tubuloglomerular feedback, with the vasoconstriction and restriction of blood flow leading to injury of tubular cells. Contrast agents cause damage to renal tubular cells in other ways specific to the type of contrast agent, leading to apoptosis and necrosis of the tubular cells. The damaged renal tubular cells detach from the basement membrane and accumulate in the tubules which causes an increase in tubular pressure, reduced glomerular filtration rate and luminal blockage. The viscosity of contrast filtered into the tubule may also contribute to increases in tubular pressure.

Contrast agents may also cause renal tubular injury by causing renal vasoconstriction mediated by inhibition of vasodilators such as nitric oxide and prostaglandins and activation of endothelin. This renal vasoconstriction, along with increases in blood viscosity caused by the contrast agents themselves, leads to renal vasoconstriction and reduced blood flow to metabolically active areas of the kidneys thus causing kidney damage. Changes in blood osmolality due to the contrast agents may lead to reduced red blood cell elasticity, thus leading to microthrombi development in the small blood vessels of the kidney thus further reducing glomerular blood flow.

Prognosis

It is unclear if CIN causes persisting decline in renal function since few studies has followed patients for more than 72 hours.^[19] In one meta-analysis the decline in renal function was shown to persist in 1.1 % of the patients with CIN.^[20]

Clinical relevance

Doubts regarding the significance of the phenomenon appeared in the scientific literature. Several studies have shown that intravenous contrast material administration was not associated with excess risk of acute kidney injury, dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity.^[1] Moreover, hydration, the most established prevention measure to prevent contrast-induced nephropathy was shown to be ineffective in the POSEIDON trial,^[21] raising further doubts regarding the significance of this disease state.^[22] A meta-analysis of 28 studies of AKI after CT with radiocontrast showed no causal relationship between the use of radiocontrast and AKI.^[2]

Notes and References

1. McDonald. Robert. McDonald. Jennifer S.. Carter. Rickey E.. Hartman. Robert P.. Katzberg. Richard W.. Kallmes. David F.. Williamson. Eric E.. December 2014 . Intravenous Contrast Material Exposure Is Not an Independent Risk Factor for Dialysis or Mortality. Radiology. 273. 3. 714–725. 25203000. 10.1148/radiol.14132418.
2. Aycock. Ryan D.. Westafer. Lauren M.. Boxen. Jennifer L.. Majlesi. Nima. Schoenfeld. Elizabeth M.. Bannuru. Raveendhara R.. Acute Kidney Injury After Computed Tomography: A Meta-analysis. Annals of Emergency Medicine. 71. 1. 44–53.e4. August 2017. 10.1016/j.annemergmed.2017.06.041. 28811122. 27167779.
3. Book: ACR Manual on Contrast Media. American College of Radiology. 2022. 978-1-55903-012-0. 40–50. 10. Post-Contrast Acute Kidney Injury and Contrast-Induced Nephropathy in Adults. 2022-08-02.
4. Mehran R, Aymong ED, Nikolsky E. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J. Am. Coll. Cardiol.. 44. 7. 1393–9. 2004. 15464318. 10.1016/j.jacc.2004.06.068. etal.
5. Book: Contrast-Induced Nephropathy. StatPearls Publishing. 2017. Kalgi Modi, Scott C. Dulebohn. 28846220 . CC-BY-4.0
6. Nyman. Ulf. Ahlkvist. Joanna. Aspelin. Peter. Brismar. Torkel. Frid. Anders. Hellström. Mikael. Liss. Per. Sterner. Gunnar. Leander. Peter. Preventing contrast medium-induced acute kidney injury. European Radiology. 28. 12. 5384–5395. 2018. 0938-7994. 10.1007/s00330-018-5678-6. 30132106. 52057355.
7. Yang. Xiaoming. Hiremath. Swapnil. Akbari. Ayub. Shabana. Wael. Fergusson. Dean A.. Knoll. Greg A.. Prevention of Contrast-Induced Acute Kidney Injury: Is Simple Oral Hydration Similar To Intravenous? A Systematic Review of the Evidence. PLOS ONE. 8. 3. 2013. e60009. 1932-6203. 10.1371/journal.pone.0060009. 23555863. 3608617. 2013PLoSO...860009H. free.
8. Subramaniam. RM. Suarez-Cuervo. C. Wilson. RF. Turban. S. Zhang. A. Sherrod. C. Aboagye. J. Eng. J. Choi. MJ. Hutfless. S. Bass. EB. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis.. Annals of Internal Medicine. 15 March 2016. 164. 6. 406–16. 26830221. 10.7326/m15-1456. free.
9. Sinert R, Doty CI. Evidence-based emergency medicine review. Prevention of contrast-induced nephropathy in the emergency department. Annals of Emergency Medicine. 50. 3. 335–45, 345.e1–2. 2007. 17512638. 10.1016/j.annemergmed.2007.01.023.
10. Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Arch. Intern. Med.. 165. 10. 1087–93. 2005. 15911721. 10.1001/archinte.165.10.1087.
11. Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR Am J Roentgenol. 2004. 1673–89. 183. 6 . 15547209. 10.2214/ajr.183.6.01831673.
12. Kellum J, Leblanc M, Venkataraman R. Renal failure (acute). Clinical Evidence. 15. 1191–212. 2006. 16973048.
13. Sadat U, Usman A, Gillard JH, Boyle JR. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials.. J Am Coll Cardiol. 2013. 62. 23. 2167–75. 23994417. 10.1016/j.jacc.2013.07.065. free .
14. Putzu. Alessandro. Berto. Martina Boscolo. Belletti. Alessandro. Pasotti. Elena. Cassina. Tiziano. Moccetti. Tiziano. Pedrazzini. Giovanni. Prevention of Contrast-Induced Acute Kidney Injury by Furosemide With Matched Hydration in Patients Undergoing Interventional Procedures. JACC: Cardiovascular Interventions. 10. 4. 355–363. 10.1016/j.jcin.2016.11.006. 28231903. 2017.
15. Mattathil. Stephanie. Ghumman. Saad. Weinerman. Jonathan. Prasad. Anand. 2017-10-01. Use of the RenalGuard system to prevent contrast-induced AKI: A meta-analysis. Journal of Interventional Cardiology. en. 30. 5. 480–487. 10.1111/joic.12417. 28870002. 27646564. 1540-8183. free.
16. Barrett BJ, Parfrey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N. Engl. J. Med.. 354. 4. 379–86. 2006. 16436769. 10.1056/NEJMcp050801.
17. Subramaniam. RM. Suarez-Cuervo. C. Wilson. RF. Turban. S. Zhang. A. Sherrod. C. Aboagye. J. Eng. J. Choi. MJ. Hutfless. S. Bass. EB. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Annals of Internal Medicine. 164. 6. 406–16. February 2016. 26830221. 10.7326/M15-1456. free.
18. Mehran . Roxana . Dangas . George D. . Weisbord . Steven D. . Contrast-Associated Acute Kidney Injury . New England Journal of Medicine . 30 May 2019 . 380 . 22 . 2146–2155 . 10.1056/NEJMra1805256.
19. Book: Ellis. JH. ACR Manual on Contrast Media. Davenport. MS. Dillman. JR. Hartman. RP. Herts. BR. Jafri. SZ. Kolbe. AB. Laroia. A. Cohan. RH. 2017. American College of Radiology. 978-1-55903-012-0. 35–46. 20 November 2020. JK. Sirlin. CB. Wang. CL. Wasserman. N. Weinreb. JC. Pahade. JH. Newhouse. L. RJ. MacDonald. Needleman.
20. Kooiman. Judith. Pasha. Sharif M.. Zondag. Wendy. Sijpkens. Yvo W. J.. Molen. Aart J. van der. Huisman. Menno V.. Dekkers. Olaf M.. 2012-10-01. Meta-analysis: Serum creatinine changes following contrast enhanced CT imaging. European Journal of Radiology. English. 81. 10. 2554–2561. 10.1016/j.ejrad.2011.11.020. 0720-048X. 22177326. 6307799 .
21. Brar. Somjot S.. Aharonian. Vicken. Mansukhani. Prakash. Moore. Naing. Shen. Albert Y.-J.. Jorgensen. Michael. Dua. Aman. Short. Lindsay. Kane. Kevin. 2014-05-24. Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the POSEIDON randomised controlled trial. Lancet. 383. 9931. 1814–1823. 10.1016/S0140-6736(14)60689-9. 1474-547X. 24856027. 7882106.
22. Web site: Contrast-Induced Nephropathy: Signal or Noise?. Medscape. John Mandrola. 2017-03-07. 2017-09-28.