1. IN THE NAME OF GOD PRESENTED BY: Dr SAHAR VAHDAT ASSISTANT PROFESSOR OF NEPHROLOGY IUMS 1 5/19/2016

2. INTRODUCTION  The administration of radiocontrast media can lead to a usually reversible form of acute kidney injury  Contrast-induced AKI, defined as an increase in creatinine ≥0.5 mg/dL or ≥25 percent over baseline within 72 hours  In most cases, there are no permanent sequelae, but there is some evidence that its development is associated with adverse outcomes 2 5/19/2016

3. Types of radiocontrast agents  first-generation agents: are ionic monomers; they are highly hyperosmolal (approximately 1400 to 1800 mosmol/kg) compared with the osmolality of plasma  Second-generation agents: such as iohexol, are nonionic monomers with osmolality (500 to 850 mosmol/kg) compared with plasma. In addition, there is an ionic low- osmolal contrast agent (ioxaglate).iohexol  The newest nonionic contrast agents: are iso-osmolal, being dimers with an osmolality of approximately 290 mosmol/kg (iodixanol is the first such agent). Thus, iso-osmolal agents have a lower osmolality than "low-osmolal" second- generation drugs.iodixanol 3 5/19/2016

4. PATHOGENESIS studies show evidence of acute tubular necrosis (ATN) The two major theories are that ATN is caused:  renal vasoconstriction resulting in medullary hypoxia, possibly mediated by alterations in nitric oxide, endothelin, and/or adenosine  a direct result of the cytotoxic effects of the contrast agents unlike other types of ATN, contrast nephropathy is usually characterized by relatively rapid recovery of renal function. (ie, within a few days), compared with a longer duration (ie, one to three weeks), as with ATN due to other causes  The degree of tubular necrosis is much less severe than seen in other settings. 4 5/19/2016

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8. History and Physical Examination History Patients usually present with a history of contrast administration 24-48 hours prior to presentation, having undergone a diagnostic or therapeutic procedure (eg, percutaneous coronary intervention [PCI]). The acute kidney injury is usually nonoliguric. Physical examination A physical examination is useful for ruling out other causes of acute nephropathy, such as cholesterol emboli (eg, blue toe, livedo reticularis) or drug-induced interstitial nephritis (eg, rash). Patients may have evidence of volume depletion or may be in decompensated heart failure. 8 5/19/2016

9. Diagnostic Considerations Conditions to consider in the differential diagnosis of CIN include the following:  Atheroembolic renal failure - More than 1 week after contrast, blue toes, livedo reticularis, transient eosinophilia, prolonged course, and lower recovery  Acute kidney injury (includes prerenal and postrenal azotemia) - There may also be associated dehydration from aggressive diuresis, exacerbated by preexisting fluid depletion; the acute kidney injury is usually oliguric, and recovery is anticipated in 2-3 weeks Acute kidney injury  Acute interstitial nephritis (triad of fever, skin rash, and eosinophilia) - Also eosinophiluria; the nephritis is usually from drugs such as penicillin, cephalosporins, and nonsteroidal anti-inflammatory drugs (NSAIDs)interstitial nephritis  Acute tubular necrosis - Ischemia from prerenal causes; endogenous toxins, such as hemoglobin, myoglobin, and light chains; exogenous toxins, such as antibiotics, chemotherapeutic agents, organic solvents, and heavy metals Acute tubular necrosis 9 5/19/2016

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11. Approach Considerations  In CIN, the serum creatinine (SCr) concentration usually: begins to increase within 24 hours after contrast agent administration, peaks between days 3 and 5 and returns to baseline in 7-10 days.  Serum cystatin C (which has been suggested as a surrogate marker of renal function in lieu of SCr) is increased in patients with CIN.  Nonspecific formed elements can appear in the urine, including:  renal tubular epithelial cells  pigmented granular casts  urate crystals  debris However, these urinary findings do not correlate with severity.  Urine osmolality tends to be less than 350 mOsm/kg.  The fractional excretion of sodium (FENa) may vary widely. In the minority of patients with oliguric CIN, the FENa is low in the early stages, despite no clinical evidence of volume depletion. 11 5/19/2016

12. Treatment & Management Hydration therapy is the cornerstone of contrast-induced nephropathy (CIN) prevention. Renal perfusion is decreased for up to 20 hours following contrast administration. Intravascular volume expansion: maintains renal blood flow preserves nitric oxideproduction prevents medullary hypoxemia enhances contrast elimination 12 5/19/2016

13. other therapies for CIN 5/19/2016 13  statins  bicarbonate  N-acetylcysteine  ascorbic acid  the adenosine antagonists theophylline and aminophylline  vasodilators  forced diuresis  and renal replacement therapy Patients with CIN should be managed in consultation with a nephrologist.

14. Hydration Therapy  Normal saline has been found to be superior to half-normal saline in terms of its enhanced ability in intravascular volume expansion.  It also causes increased delivery of sodium to the distal nephron, prevents renin-angiotensin activation, and thus maintains increased renal blood flow.  In terms of route of administration, oral fluids, while beneficial, are not as effective as intravenous hydration. 14 5/19/2016

15. Cont..  adequate intravenous volume expansion with isotonic crystalloids (1-1.5 mL/kg/h), 3-12 hours before the procedure and continued for 6-24 hours afterward, decreases the incidence of CIN in patients at risk.  For hospitalized patients, volume expansion should begin 6 hours prior to the procedure and be continued for 6-24 hours postprocedure.  For outpatients, administration of fluids can be initiated 3 hours before and continued for 12 hours after the procedure.  Postprocedure volume expansion is more important than preprocedure hydration. It has been suggested that a urine output of 150 mL/h should guide the rate of intravenous fluid replacement 15 5/19/2016

16. Hydration with Saline Guidelines IVF = 1 mL/kg/hr (MAX 100 ml/hr) 12 hours pre & 12 hours post contrast* (24 hour total infusion duration) *NS preferred IVF CHF or left ventricular ejection fraction (LVEF) < 40%? 0.5 ml/kg/hr (max 50 ml/hr) 12 hrs pre & post contrast (24 hour total infusion duration) Emergent procedure? Fluid bolus of 500-1000 ml prior to procedure. Hydration during procedure and/or 12 hrs after if possible (dependent on clinical status) 16 5/19/2016

17. Statins  Statins are widely used in coronary artery disease (CAD) for their pleiotropic effects (favorable effects on endothelin and thrombus formation, plaque stabilization, and anti-inflammatory properties)  One meta-analysis showed that in patients undergoing coronary angiography/percutaneous intervention, short-term statins reduced the incidence of CIN and should be used even in patients with low LDL cholesterol levels  Another meta-analysis demonstrated that preprocedural rosuvastatin treatment could significantly reduce the incidence of contrast-induced acute kidney injury. However, rosuvstatin treatment did not seem to be effective for preventing contrast- induced acute kidney injury in patients with chronic kidney disease who underwent elective cardiac catheterization 17 5/19/2016

18. Bicarbonate Therapy  Bicarbonate therapy alkalinizes the renal tubular fluid and, thus, prevents free radical injury.  infusion of sodium bicarbonate at the rate of 3 mL/kg/hour an hour before the procedure, continued at 1 mL/kg/hour for 6 hours after.  Hydration with sodium bicarbonate has been found by some researchers to be more protective than normal saline alone..  In addition, hydration with sodium bicarbonate was found to be more effective in emergency coronary imaging and high- risk patients than in elective coronary imaging. 18 5/19/2016

19. Bicarbonate Dosing Guidelines IVF = 150 meq of sodium bicarbonate in 850 ml or1 liter of D5W 3 ml/kg bolus (MAX 300 ml) 1 hour prior to procedure AND 1 mL/kg/hour (MAX 100 ml/hr) during and for 6 hours post-procedure Glycemic control issues (including patients with diabetes)? Consider mixing sodium bicarbonate in 1 liter of sterile water instead of D5W 19 5/19/2016

20. N-acetylcysteine  NAC is acetylated L-cysteine, an amino acid. an excellent antioxidant and scavenger of free oxygen radicals. It also enhances the vasodilatory properties of nitric oxide  The standard oral NAC regimen consists of 600 mg twice daily for 24 hours before and on the day of the procedure. Higher doses of 1 g, 1200 mg, and 1500 mg twice daily have also been studied, with no significant dose-related or route-related (oral vs intravenous) difference NAC has very low oral bioavailability 20 5/19/2016

21. Cont..  NAC is routinely administered because of its low cost, lack of adverse effects, and potential beneficial effect  It was suggested that the beneficial effect of NAC in CIN is related to its ability to lower serum creatinine (SCr) rather than to improved glomerular filtration rate (GFR).  It was believed that NAC directly reduces SCr by increasing creatinine excretion (tubular secretion), decreasing its production (augments activity of creatine kinase), or interfering with its laboratory measurement, enzymatic or nonenzymatic (Jaffe method). 21 5/19/2016

22. Tolerating PO intake? 600-1200 mg capsules PO Q12h X 4 doses 2 doses pre-contrast and 2 doses post-contrast is optimal Feeding tube or NG-access? Acetylcysteine 600-1200 mg (3 mL of 20% soln.) liquid PT/NG Q12h x 4 doses total Emergent Procedure? 1 dose before and 3 doses post cath or procedure is acceptable (Q12h x 4 doses total) IV Acetylcysteine? Based upon the lack of convincing evidence of benefit and the potential risk of anaphylactoid reactions, we suggest not using intravenous acetylcysteine for the prevention of contrast nephropathyacetylcysteine 22 5/19/2016 Acetylcysteine Dosing Guidelines

23. IV Alternatives: 5/19/2016 23 IV Alternatives: Ascorbic Acid 3 gm IV x1 dose 2 hours prior to procedure, then 2 gm IV BID x 2 doses post- procedure Aminophylline 300 mg IV x1 (infused over 1 hour) prior to procedure

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25. Renal Replacement Therapy  Fewer than 1% of patients with CIN ultimately go on to require dialysis.  the number being slightly higher in patients with underlying renal impairment (3.1%) and in those undergoing primary percutaneous coronary intervention (PCI) for myocardial infarction (3%).  However, in patients with diabetes and severe renal failure, the rate of dialysis can be as high as 12%.  Patients who get dialyzed do considerably worse, with in- hospital mortality rates of 35.7% (compared with 7.1% in the nondialysis group) and a 2-year survival rate of only 19%. 25 5/19/2016

26. CONT.. 50% of the low-osmolarity contrast agent iomeprol is eliminated within 2 hours in healthy subjects, compared with 16-84 hours in patients with severe renal impairment. risk of acute damage from contrast is therefore greatest in patients with chronic kidney disease (CKD). This can be explained by the increase in single-nephron GFR and, thus, the filtered load of contrast per nephron. 26 5/19/2016

27.  residual renal function, in fact, plays a big role in their outcome, more so in patients on peritoneal dialysis. CM can be effectively and efficiently removed by hemodialysis (HD). Factors that influence CM removal include:  blood flow  membrane surface area  molecular size  transmembrane pressure  and dialysis time High-flux dialysis membranes with blood flows of between 120-200 mL/min can remove almost 50% of iodinated CM within an hour and 80% in 4 hours. In view of the limited benefit of therapies such as hydration, bicarbonate and NAC, dialysis may seem like the definitive answer. CONT.. 27 5/19/2016

28.  do NOT recommend routine hemofiltration or hemodialysis for the prevention of contrast nephropathy in patients with CKD.  There is no indication for prophylactic dialysis for the prevention of volume overload in dialysis-dependent patients  Furthermore, there are no studies that support immediate dialysis after intravascular contrast media administration in order to preserve residual renal function or limit the risk of allergic reaction in hemodialysis patients  The issue of whether dialysis should be performed within 24 hours following contrast media administration or can safely wait until the next dialysis treatment remains unclear.. 28 5/19/2016

29. cont..  Dialysis immediately after contrast administration has been suggested for patients already on long-term HD and for those at very high risk of CIN.  The only condition in which HD might be argued to have a beneficial role is in patients on peritoneal dialysis who rely on their residual renal function. In this setting, HD performed soon after CM administration may provide enhanced removal and therefore protect residual renal function.  It should be noted, however, that these patients on peritoneal dialysis would therefore need an additional HD procedure with concomitant vascular access, as the clearance with peritoneal dialysis would be far too slow to offer any protection. 29 5/19/2016

30. CONT… advantage of CRRT is the lack of delay in its institution, contrast clearance rates would be 1 L/h, substantially less than standard HD. Furthermore, continuous venovenous hemofiltration is expensive, highly invasive, and requires trained personnel; the procedure itself needs to be performed in the intensive care unit (ICU). 30 5/19/2016

31. Other Therapies  Ascorbic acid: antioxidant properties, counter the effect of free radicals and reactive oxygen species. One study found that oral ascorbic acid administered in a 3-g dose preprocedure and two 2-g doses postprocedure was associated with a 62% risk reduction in CIN incidence.  Theophylline and aminophylline :adenosine antagonists that counteract the intrarenal vasoconstrictor and tubuloglomerular feedback effects of adenosine. significant effect in preventing CIN in high-risk patients. However, their use is limited by their narrow therapeutic window and adverse effects profile  Vasodilators: calcium channel blockers, dopamine/fenoldopam, atrial natriuretic peptide, and L-arginine, have a favorable effect on renal hemodynamics. However, their use for CIN prevention has not been borne out by most controlled trials, and they are not routinely recommended at this point.  Furosemide and mannitol : worsen CIN by causing dehydration in patients who may already have intravascular volume depletion. Their use at this time is discouraged. 31 5/19/2016

32. Deterrence and Prevention Risk Factors: Hypotension (SBP < 80 mmHg) Heart Failure (NYHA III/IV) Use of intra-aortic balloon pump (IABP) Preexisting renal dysfunction **SCr>1.5 mg/dl OR CrCl <60 ml/min** Age ≥ 75 years Diabetes Hematocrit < 39% for men, or < 36% for women Dehydration Concomitant use of nephrotoxic drugs and/or renal perfusion reducing agents **ACEI’s, Aminoglycosides, Vancomycin, Diuretics, NSAID’s. 32 5/19/2016

33. RISK Assessment Low Risk: 0 Risk Factors Moderate Risk: 1 Risk Factor High Risk: ≥ 2 risk factors OR SCr > 2.0 and/or CrCl < 40 33 5/19/2016

34.  In patients with a moderate to severe risk of CIN, eGFR should be estimated by either the MDRD formula or the Cockroft-Gault formula and then measured again 24-48 hours after contrast administration.  In the emergency setting, where the benefit of very early imaging studies outweighs that of waiting, the imaging procedure can be carried out without an initial estimation of SCr or eGFR.  Intra-arterial administration of iodinated CM poses a greater risk for CIN than does the intravenous approach. For patients at an increased risk for CIN receiving intra- arterial contrast, nonionic iso-osmolar agents (iodixanol) are associated with the lowest risk of CIN.  The amount of contrast used during the procedure should be limited to as little as possible and kept under 100 Ml  The risk of CIN increases by 12% for each 100 mL of contrast used beyond the first 100 mL  Most angiographic diagnostic studies usually require 100 mL of contrast, compared with 200-250 mL for angioplasty. 34 5/19/2016

35.  The length of time between two contrast procedures should be at least 48-72 hours. Rapid repetition of contrast administration has been found to be a univariate risk factor for CIN.  Potentially nephrotoxic drugs (eg, NSAIDs, aminoglycosides, amphotericin B, cyclosporin, tacrolimus) should be withdrawn at least 24 hours beforehand, in patients at risk (eGFR < 60 mL/min).  Metformin, though not nephrotoxic, should be used prudently, because if renal failure does occur, there is risk of concomitant lactic acidosis. Therefore, metformin should be stopped at the time of the procedure and resumed 48 hours later if renal function remains normal.  (ACE)I and (ARBs) cause a 10-15% rise in SCr by reducing intraglomerular pressure. While they should not be started at this time, whether they should be discontinued remains a matter of debate. 35 5/19/2016

36. MR contrast agents there are two major concerns with gadolinium-based chelates: ●Among patients with moderate and particularly severe kidney disease, the possible development of the severe syndrome of nephrogenic systemic fibrosis (NSF). ●The possible development of nephrotoxicity, similar to that seen with iodinated contrast agents. 36 5/19/2016

37. Cont..  when used in small doses for MR examinations, have little or no nephrotoxicity  gadolinium-based contrast media can be associated with nephrotoxicity when given at high doses (>0.3 mmol/kg) for use as a contrast agent in standard (non-MR) digital subtraction angiography  among patients with moderate to severe kidney disease (dialysis dependent or eGFR <30 mL/min), the administration of gadolinium has been associated with the potentially severe syndrome of NSF. In such patients, gadolinium should be avoided, if possible.  In such patients, we prefer the risk of radiocontrast nephropathy with iodinated contrast media, using all of the preventive measures that are available, to the risk of the much more severe complication of NSF. 37 5/19/2016

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