Contrast-induced Nephropathy - Just an Iatrogenic Kidney Disease?

Login or register to view PDF.
The Problem of Contrast-induced Nephropathy

Contrast-induced nephropathy (CIN) is an increasingly common cause of acute renal failure in both hospitalized patients and out-patients. The growth in contrast-enhanced imaging and interventional procedures is one cause of the increased incidence of CIN. An aging patient population, with more comorbidities such as reduced renal function, may be another reason for the higher incidence of CIN.

Definitions of CIN vary, but most investigators accept that a 25% or greater increase in serum creatinine, or decrease in calculated creatinine clearance in the appropriate clinical setting, defines CIN. The appropriate setting is:

  • exposure to intravenous or intra-arterial contrast;
  • a rise in creatinine within 24-48 hours of contrast exposure; and
  • the absence of other explanations for acute renal failure such as nephrotoxins, hypotension, urinary obstruction, or atheromatous emboli.

CIN is usually self-limited, with serum creatinine levels peaking in three to five days and gradually returning to baseline levels within seven to 10 days.2 Most CIN patients are non-oliguric and examination of the urinary sediment reveals only granular casts without red or white cells. Proteinuria is rarely present by dipstick testing. Urine sodium is often low, suggesting a prerenal physiology.3 A small percentage of patients with CIN (<5%) may require dialysis until renal function recovers.

Pathogenesis of CIN and Risk Factors

For the majority of patients with CIN, the transient rise in serum creatinine and eventual recovery to baseline mirrors the changes in renal function that are associated with volume depletion and pre-renal azotemia.This has led to important misunderstandings regarding the pathogenesis and prognosis associated with CIN. CIN represents a combination of toxic and ischemic injury to the kidney, predominately in the medulla. Decreases in medullary blood flow and medullary oxygen tension follow exposure to contrast. Increases in vasoconstrictor hormones, such as endothelin and adenosine, and loss of vasodilatory factors such as nitric oxide, may contribute to the vasoconstriction that reduces medullary blood flow. At the same time that medullary flow and oxygenation are reduced, an increase in sodium is delivered to the medullary tubules because of the osmotic effect of the contrast agent. The loop of Henle increases sodium reabsorption in response to this load (an oxygen-requiring process). The increase in oxygen requirements coupled with decreased oxygen availability results in ischemic injury.

Since only a minority of patients exposed to contrast media suffer this ischemic injury, there must be certain factors that predispose some individuals to this form of injury (see Figure 1).

A variety of characteristics may predispose a patient to a higher incidence of CIN. Most importantly, pre-existing renal impairment is a risk factor - the worse the baseline renal function, the higher the risk. A general rule of thumb is that the risk is 10 times the serum creatinine. Diabetes, particularly with renal impairment, is another risk factor. Volume depletion, congestive heart failure, and the use of diuretics are also risk factors for CIN.

These factors both have renal physiology set toward vasoconstriction. Congestive heart failure, use of diuretics, and volume depletion are all associated with neurohumoral changes that predispose to renal sodium retention and vasoconstriction. Chronic kidney disease and diabetes are likewise associated with endothelial dysfunction and decreased vasodilatory responses. With the further burden of contrast-induced decreases in renal blood flow and increases in demand for oxygen, renal failure ensues.

Outcomes in Patients with CIN

The occurrence of CIN may tell us something about the state of the vasculature throughout the body. Levy et al. highlighted the increased in-hospital mortality seen in those who developed CIN versus those matched for renal function who did not.4 After adjusting for comorbidities, the risk of mortality was 5.5-fold higher in those who developed CIN. However, the increased mortality was related to sepsis, hemorrhage, and pulmonary complications, not to renal failure per se. Subsequent studies have confirmed the increase in in-hospital as well as one-year5 and five-year mortality22 in patients undergoing percutaneous coronary interventions who developed CIN. Clearly, mortality at one year cannot be directly related to the development of CIN. Rather, mortality in these patients was related to increased incidence of myocardial infarction. Of note, increased mortality has been noted primarily in those patients who had at least a 25% increase in creatinine following contrast exposure, supporting the clinical use of this definition of CIN.23

In addition to short- and long-term implications for survival, CIN is associated with increased length of stay, hospital costs, and delay in subsequent procedures. Since the timing of CIN is predictable, many efforts have been made to prevent the occurrence of CIN.24

Strategies for Prevention of CIN

Most strategies for prevention take advantage of the pathogenesis of the CIN. Preventing volume depletion and activation of renal vasoconstrictive forces is one of the most widely accepted strategies. Discontinuation of diuretic therapy and volume replacement with saline reduces the incidence of CIN by more than 50%.

In a prospective trial in high-risk patients, CIN occurred in 11% of those who received saline, 26% of those who received saline and mannitol, and 46% of those who received saline and furosemide1 (see Figure 2). The ideal volume replacement solution is in debate.The original studies used half normal saline but subsequent studies suggest superiority of normal saline25 or possibly isotonic sodium bicarbonate. In a recent study, the infusion of 3mL/kg/h x1 of an isotonic solution of sodium bicarbonate followed by 1mL/kg/h x6 was associated with a 2% incidence of CIN in high risk patients compared with 17% in a group randomized to normal saline.16

Attempts to induce renal vasodilation with a variety of substances has been generally unsuccessful. Part of the problem may be the non-selectivity of the renal vasodilation. Most of the effect is in the cortex, which may, in effect, steal blood flow from the medullary, the primary site of injury. Dopamine, atrial natriuretic peptide, and fenoldopam (a dopamine agonist) have all failed to reduce the rate of CIN when subjected to multicenter, prospective, randomized trials. Single center trials with calcium channel blockers and adenosine antagonists have been somewhat successful but have not been subjected to rigorous multicenter testing.

N-acetylcysteine (Mucomyst®) is both a renal vasodilator and antioxidant.A number of single center trials have reported a reduction in the incidence of CIN with pretreatment the day before and the day of contrast exposure. An equal number of reports fail to show a benefit (26-30). The differences between studies may be related to dose (600 twice daily (bid) versus 1,200 bid), timing (day before versus day of), route of administration (oral versus intravenous), and other confounding factors such as the volume of contrast administered. Since acetylcysteine is inexpensive and has few side-effects, its use has been widespread despite the lack of compelling evidence in support of its benefit.26

The type and amount of contrast agent is also important. Early experience suggested that high osmolar, ionic agents (diatrizoate) were more nephrotoxic than low-osmolar, non-ionic contrast agents. A meta-analysis of 39 studies found that patients with renal insufficiency had a reduced incidence of CIN when low-osmolar agents were used. No difference in CIN was noted in those with normal renal function.27 Low osmolar and isomolar agents have largely replaced the older high osmolar agents, predominantly because of reduced rates of immediate systemic reactions to the infusion of contrast. Direct head-to-head comparisons between different members of the low and isomolar agents are few. One recent study compared iodixanol (non-ionic dimer, iso-osmolar) with iohexol (non-ionic monomer, low osmolar) in patients with renal impairment and diabetes. In this high-risk group, iodixanol was associated with a significantly lower rate of CIN as compared with iohexol.6

Studies with a single agent in high risk patients undergoing cardiac catheterization or peripheral angiography suggest that both iodixanol and iopamidol may have a lower rate of CIN compared with iohexol (see Figure 3). The mechanism underlying these differences is currently unknown, however, and patient populations may differ somewhat between studies. Additionally, the volume of contrast is an important risk factor for the development of CIN. The risk of CIN is proportional to the volume of contrast infused. Long, complicated interventions and multiple contrast studies in a short period of time should be avoided in high-risk patients.

Finally, a recent study used hemofiltration to remove contrast at the time of PCI.28 In a small group of patients, this intervention reduced the incidence of CIN, defined as a 25% increase in serum creatinine. However, the study is seriously flawed as the volume of contrast used was very high (about 250mL) and the hemofiltration lowered serum creatinine relative to baseline. The increment in serum creatinine changes following hemofiltration was similar to those who didnÔÇÖt receive the hemofiltration. The use of such an invasive and expensive intervention is unwarranted at this time.

In summary, CIN is an all too frequently observed complication of the use of contrast agents. Its occurrence tells us something about the sensitivity of the kidney to ischemic injury.While the kidney may be the 'canary in the cageÔÇÖ, CIN tells us something about systemic vascular health. A number of strategies to prevent CIN are recommended (see Figure 4). Judicious use of contrast - avoidance in contrast-enhanced procedures in favor of other diagnostic tools in high risk patients - and use of low-osmolar agents and minimum volumes is one part of minimizing the risk. Volume repletion - discontinuation of diuretics, infusion of sodium chloride (or possibly sodium bicarbonate) - is another step. Avoidance of vasoconstrictors (non-steroidal anti-inflammatory drugs - NSAIDs) and use of acetylcysteine are a final step. Employing all three steps simultaneously will minimize the risk of CIN. Ôûá

References
  1. Solomon R,Werner C, Mann D et al., "Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents", N. Engl. J. Med. (1994), 331: pp. 1,416-1,420.
    Crossref | PubMed
  2. Solomon R,"Contrast-medium-induced acute renal failure", Kidney Int. (1998), 53: pp. 230-242.
    Crossref | PubMed
  3. Fang L, Sirota R A, Ebert T H and Lichenstein N S,"Low fractional excretion of sodium with contrast media induced acute renal failure", Arch. Int. Med., (1980), 140: pp. 531-533.
    Crossref | PubMed
  4. Levy E,Viscoli C M, Horwitz R I, "The effect of acute renal failure on mortality,A cohort analysis", JAMA, (1996), 275: pp. 1,489-1,494.
    Crossref | PubMed
  5. McCullough P,Wolyn R, Rocher L L, et al.,"Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality", Am. J. Med., (1997), 103: pp. 368-375.
    Crossref | PubMed
  6. Aspelin P, Aubry P, Fransson S, et al., "Nephrotoxic effects in high-risk patients undergoing angiography", N. Engl. J. Med. (2003), 348: pp. 491-499.
    Crossref | PubMed
  7. Baker C,Wragg A, Kumar S, et al., "A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study", J.Am. Coll. Cardiol., (2003), 41: pp. 2,114-2,118.
    Crossref | PubMed
  8. Boccalandro F,Amhad M, Smalling R W, et al.,"Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast", Cathet. Cardiovasc. Interv., (2003), 58: pp. 336-341.
    Crossref | PubMed
  9. Briguori C, Manganelli F, Scarpato P, et al., "Acetylcysteine and contrast agent-associated nephrotoxicity", J.Am. Coll. Cardiol. (2002), 40: pp. 298-303.
    Crossref | PubMed
  10. Chalmers N and Jackson R W, "Comparison of iodixanol and iohexol in renal impairment", Br. J. Radiol., (1999), 72: pp. 701-703.
    Crossref | PubMed
  11. Diaz-Sandoval L, Kosowsky B D, Losordo D W,"Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial)", am. J. Cardiol., (2002), 89: pp. 356-358.
    Crossref | PubMed
  12. Durham J, Caputo C, Dokko J, et al.,"A randomized controlled trial of N-acetylcysteine to prevent contrast nephropahty in cardiac angiography", Kidney Int., (2002), 62: pp. 2,202-2,207.
    Crossref | PubMed
  13. Goldenberg I, Shechter M, Matetsky S, et al.,"Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrastinduced nephropathy following coronary angiography: a randomized controlled trial and review of the current literature", Eur. Heart J. (2004), 25: pp. 212-218.
    Crossref | PubMed
  14. Hans S, Hans B A, Dhillon R, et al.,"Effect of dopamine on renal function after arteriography in patients with pre-existing renal insufficiency", Am. Surgeon, (1998), 64: pp. 432-436.
    PubMed
  15. Kay J, Chow W H, Chan T M, et al., "Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention", JAMA, (2003), 289: pp. 553-558.
    Crossref | PubMed
  16. Merten G, Burgess W P, Gray L V, et al, "Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial", JAMA, (2004), 291: pp. 2,328-2,334.
    Crossref | PubMed
  17. Oldemeyer J, Biddle W P,Wurdeman R L, et al.,"Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography", Am. Heart J., (2003), 146: p. e23.
    Crossref | PubMed
  18. Rudnick M, Goldfarb S,Wexler L, et al., "Nephropathy of ionic and nonionic contrast media in 1196 patients: a randomized trial", Kidney Int., (1995), 47: pp. 254-261.
    Crossref | PubMed
  19. Shyu K, Cheng J J and Kuan P,"Acetylcysteine protects against renal damage in patients with abnormal renal function undergoing a coronary procedure", J.Am. Coll. Cardiol., (2002), 40: pp. 1,383-1,388.
    Crossref | PubMed
  20. Taliercio C,Vlietstra R E, Ilstrup D M, et al.,"A randomized comparison of nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography", J.Am. Coll. Cardiol., (1991), 17: pp. 384-390.
    Crossref | PubMed
  21. Huber W, Schipek C, Ilgmann K, et al.,"Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficienc", Am. J. Cardiol. (2003), 91: pp. 1,157-1,162.
    Crossref | PubMed
  22. Rihal C,Textor S C, Grill D E, et al., "Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention", Circulation, (2002), 105: pp. 2,259-2,264.
    Crossref | PubMed
  23. Gruberg L, Mintz G S, Mehran R, et al., "The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency", J.Am. Coll. Cardiol. (2000), 36: pp. 1,542-1,548.
    Crossref | PubMed
  24. Iakovou I, Dangas G, Lansk, A J, et al., "Incidence, predictors, and economic impact of contrast induced nephropathy: results in 8,628 patients treated with percutaneous coronary interventions", J.Am. Coll. Cardiol. (2002), 39: p. 2A.
  25. Mueller C, Guerkle G, Buettner H, et al., "Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angiography", Arch. Int. Med., (2002), 162: pp. 329-336.
    Crossref | PubMed
  26. Kshirsagar A, Poole C, Mottl A, et al.,"N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials", J.Am. Soc. Nephrol., (2004), 15: pp. 761-769.
    Crossref | PubMed
  27. Barrett B, Carlisle E J, "Metaanalysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media", Radiology, (1993), 188: pp. 171-178.
    Crossref | PubMed
  28. Marenzi G, Marana I, Lauri G, et al.,"The prevention of radiocontrast-agent-induced nephropathy by hemofiltration", N. Engl. J. Med., (2003), 349: pp. 1,333-1,340.
    Crossref | PubMed