Prevention of contrast-induced acute kidney injury induced by angiography

 

CONTRAST NEPHROPATHY

 

Prevention of contrast-induced acute kidney injury induced by angiography
 

 

Abbreviations:

o   Aa: ascorbic acid.

o   AC: acetyl cysteine.

o   ACC/AHA: American College of Cardiology/American Heart Association.

o   ACEi: angiotensin-converting enzyme inhibitors.

o   AKI: Acute kidney injury.

o   AMI: acute myocardial infarction.

o   ANP: Atrial natriuretic peptide.

o   APO: pulmonary edema.

o   ARBs: angiotensin receptor blockers.

o   ATN: acute tubular necrosis.

o   C.I.: contraindications.

o   CA-AKI: Contrast-associated AKI.

o   CIN: contrast-induced nephropathy.

o   CKD: chronic kidney disease.

o   Dc Np: Diabetic nephropathy

o   DD: differential diagnosis.

o   eGFR: estimated GFR.

o   HDX: hemodialysis.

o   HF/HDX: hemofiltration or hemodialysis

o   LVEDP: left ventricular end-diastolic pressure.

o   MM: multiple myeloma.

o   MR: mortality.

o   Na⁺HCO₃: Sodium bicarbonates.

o   NSAIDs: nonsteroidal anti-inflammatory agents.

o   PCI: percutaneous coronary intervention.

o   PCIs: percutaneous coronary interventions.

o   Prox: prophylactic

o   RCT: randomized controlled trial.

o   RI: renal impairment.

o   RIPC: ischemic preconditioning.

o   RRT: renal replacement therapy.

o   RRT: renal replacement therapy.

o   Sln: Saline.

o   Sn & Sm: signs and symptoms.

o   USS: Ultrasound scanning.

o   UO: urine output.

o   VC: vasoconstriction.

o   ACR: albumin-to-Cr ratio

 

AKI that can be observed shortly after contrast media could or could not be attributed to contrast administration. "Contrast-associated AKI (CA-AKI)" is a general term referring to AKI seen shortly after iodinated material use and may or may not be a direct causative related to contrast material. CI-AKI," previously named CIN," is a more specific term referring to the CA-AKI diagnosed after a thorough clinical assessment, to be causally attributed to contrast administration. This term “CA-AKI” is coincident to current clinical assessment for other possible AKI etiology has not been engaged or other causes of AKI cannot be currently excluded. Moreover, CA-AKI can be also referred to rising SCr (or drop in eGFR) after contrast media in research work.

Major clinical criteria:

o   Rising SCr (mild) generally seen within 24-48 h. after iodinated contrast.

o   Mostly non-oliguric. Oliguria may be seen with severe AKI or underlying CKD.

o   Urinary sediment: classic ATN: muddy brown granular- epithelial cell cast-free tubular epithelial cell.

CI-AKI ptn should be subjected to a full detailed history & physical testing with a urine microscopy for urinary sediment to recognize findings suggesting an alternate etiology. Oliguric ptns with severe AKI (requiring RRT) may be amenable to have an alternate causes of AKI. An USS is not typically mandated, despite it may be required to exclude obstructive causes of AKI especially if Dgx of CI-AKI still uncertain (e.g., oliguria, severe AKI). Proteinuria in CI-AKI is typically lacking or mild (unless ptn proteinuric at background). However, the finding of albuminuria (via dipstick or ACR) does not exclude CI-AKI. CI-AKI is a clinical Dgx primarily based on TWO criteria:

o   Rising SCr upon 1^st 24-48 h.s after contrast.

o   Reasonably excluded other factors of AKI

Renal biopsy is generally not required for Dgx of CI-AKI, as ATN pathology is usually focal & non-specific, in addition CI-AKI is short termed one. However, as with USS, biopsy may be rarely indicated to exclude other causes of AKI if Dgx of CI-AKI still uncertain.

DD includes, kidney atheroemboli (with intra-arterial contrast testing), ischemic ATN, acute interstitial nephritis, and pre-renal alterations induced by adding of diuretics, ACEi or ARBs after contrast study. As many AKI etiologies, the management of CI-AKI is mainly supportive including removal and holding other possible kidney insults, hemodynamic & electrolyte evaluation and management, proper dose adjusting for the degree of decline in GFR, and, with severely deteriorated kidney function, management of uremic Sn & Sm. Ptns with CI-AKI usually expressing a mild decline in GFR that is mostly improving within 3-7 days. Most ptns resumed their baseline eGFR. DX is rarely indicated for CI-AKI.  

 

 Despite CI-AKI is mostly reversible, it can be complicated by adverse outcome. The reported sequelae of CI-AKI is much robust with arterially administrated route as compared to the venous route. This difference can be attributed to the difference in ptn populations (ptns requiring arterial contrast are more likely   expressing many co-morbid diseases that augment the likelihood of AKI) or the difference in nephrotoxicity of intra-arterial contrast is more robust. Prevention of arterial contrast-induced CI-AKI will be covered here.  

 EPIDEMIOLOGY

The observed incidence of CI-AKI is variable affected by AKI definition, the presence/absence of risk factor(s) (underlying CKD), magnitude and type of used agents, and the type of radiologic testing. Ptns with no risk factors (CKD in particular), their risk of CI-AKI is unnoticed (i.e., ≤1 %). Whilst others with risk factors (particularly DM & CKD), their reported risk after coronary angiography with or with no intervention = 10-30 %.  

Major risk factors: are either ptns related or procedure related.

Ptn-related factors for CI-AKI include:

1)    CKD (particularly Dc Np),

2)    Diminished kidney perfusion from HF,

3)    Hypovolemic/hemodynamic unstable ptns,

4)    MM (Myeloma kidney).

Procedure-related factors include:

1)    Dye dosage,

2)    Type of contrast agents, &

3)    Specified procedure (intra-arterial vs IV & interventional vs diagnostic angio-study).

Arterial study of contrast that is of a higher risk than venous ones.  

1)    CKD: Incidence of CI-AKI is higher in CKD and increasing with the higher intensity of renal dysfunction. The increasing risk is likely continues with the dropping in eGFR. However, the threshold of GFR at which the risk is more evident still uncertain. Study: estimating the risk with mild/moderate CKD, 289 ptns with eGFR: 30-59 mL/min/1.73 m², % AKI = 4.2 % after intra-arterial contrast. Severe CKD (= eGFR <30 mL/min/1.73 m²) were excluded. Study: 124 ptns with SCr ≥3.0 mg/dL (265 mmol/L) (average eGFR <30 mL/min/1.73 m²), % AKI after PCIs = 31 %. Proteinuria augment the risk more with declined eGFR. Prospective study: 70 CKD ptns (CKD = eGFR <60 mL/min/m² and/or proteinuria), AKI observed after angiography in 62 % of ptns + proteinuria >1 g./d. vs 21 % in those with proteinuria <1 g./d.  

2)    Dc Np + low eGFR: Dc ptns are at increasing risk as compared to non- Dc ptns. RCT: 250 ptns with SCr >1.5 mg/dL (133 micromol/L), a high % of AKI was seen among Dc ptns as compared to non- Dc ptns (33 vs 12 %, resp). Ptns with normal kidney function, 2 studies: DM does not augment the risk of CI-AKI. RCT: 341 ptns with SCr ≤1.5 mg/dL (133 mmol/L): no difference in % of CI-AKI between Dc & non- Dc ptns. Review: 1826 ptns, DX-requiring AKI seen after interventional coronary angiography in 19.5 % of Dc ptns vs 12.8 % of non-Dc CKD ptns; No ptn with CrCl >47 mL/min developed DX-requiring AKI.

3)    Dose/type of contrast media: Low dose (<125 mL) of contrast is safe, despite not entirely free of risk. Minimal amount of contrast (<10 mL) have been safely tried with sever kidney disease to examine A/V fistula. However, Dc ptns with SCr >5 mg/dL (440 micromol/L) may be at increased risk for as little as 20-30 mL of contrast. Type of contrast media can impact the risk. Contrast media could be either ionic or nonionic with varied osmolality. Older agents (1^st generation) were ionic/hyperosmolal compared to plasma (1400-1800 mosmol/kg) and rarely used today and more nephrotoxic as compared to current agents.

Currently used agents:

o   Low-osmolal agents: with lowered osmolality < 1^st generation radiocontrast agents but still higher osmolality (500-850 mosmol/kg) as compared to plasma. Commonly used low-osmolal agents including non-ionic agents (iohexol, ioversol & iopamidol) and the ionic agent, ioxaglate.

o   Iso-osmolal agents: Only one iso-osmolal agent (iodixanol) is available. It is non-ionic & iso-osmolal with plasma (290 mosmol/kg). The lowered risk of new agents is likely attributed to the {lowered osmolality + lack of charge}. The exact role of charge vs osmolality are difficult to recognize as most reports compared non-ionic low-osmolal agents vs ionic hyperosmolal media. However, a benefit of low osmolality was observed in one study: ionic low-osmolal ioxaglate is less toxic compared to ionic hyperosmolal media (1500-1800 mosmol/kg).

Among new agents, the iso-osmolal agent iodixanol has been supposed to show a lowered risk of AKI than low-osmolal agents, especially iohexol, among high-risk ptns. Meta-analysis: 25 RCT comparing iodixanol with a diverse g. of low-osmolal media (72 % with RI or DM) reported a moderate decline in risk of AKI with iodixanol. There was no difference in the eventual risks for RRT, CVS events, or death. It is possible that iohexol carries a higher risk of AKI compared with non-iohexol low osmolal media. Trial: comparing iodixanol & iohexol in 129 high-risk Dcs & CKD (mean SCr 1.5 mg/dL [133 micromol/L]) undergoing angiography, iodixanol showed a lowered incidence of AKI (3 vs 26 % with iohexol). However, 3 trials that compared iodixanol with 2 other non-ionic low-osmolal contrast media (ioversol & iopamidol) showed no difference between g. in the rate of AKI. Moreover, a meta-analysis of 16 RCT suggested that iodixanol showed lowered risk in CKD ptns receiving contrast if compared with iohexol but not if compared with other non-ionic low-osmolal contrast media. These data suggest that the benefit of iodixanol as compared to iohexol may denotes a unique nephrotoxic impact of iohexol.  

Specific radiologic procedure: The highest observed risk for AKI can be seen with (rather than diagnostic) coronary angiography (esp. interventional AMI). This could be attributed to the higher volume of agents used in interventional maneuvers + hemodynamic instability seen with AMI. Most reports have shown quite lowed risk of AKI observed with contrast CT scan (i.e., IV. contrast) is, even with the presence of CKD.

Other risk factors: may include hyperglycemia & the use of ACEi/ARBs. Hyperglycemia may augment the risk for CI-AKI independently of comorbid DM. Study: adjusted risk of AKI after angiography increasingly higher with elevated glucose with no diagnosed DM. No rise in glucose-associated risk with established DM. The impact of ACEi and/or ARBs on the incidence of CI-AKI is not clear.  Retrospective study: 5299 ptns proceed to percutaneous intervention, ACEi or ARB use contributes to AKI evolution. However, RCT: 220 ptns, eGFR of 15-60 mL/min/1.73 m²: no difference in the rate of CI-AKI development between ACEi and/or ARBs users before angiography and the cohort with similar decline in eGFR but not on ACEi and/or ARBs. Moreover, it is not obvious whether ACEi/ARB withdrawal before angiography will provide any protective benefit.

PREVENTION: measures should be focused on ptns receiving intra-arterial contrast. It is crucial to consider that many trials evaluating preventive measures have used small, transient rise in SCr as endpoint (e.g., ≥0.5 mg/dL [44.2 micromol/L] or ≥25-50 % above baseline). However, trials suggesting that CIN, considering this attitude, is accompanied with significant in-hospital as well as long-term MR.

Risk ptns:

o   eGFR <60 mL/min/1.73 m² + significant proteinuria (= albuminuria >300 mg/d, corresponding to proteinuria > 500 mg/d).

o   eGFR <60 mL/min/1.73 m² + co-morbid DM, HF, liver failure, or MM.

o   eGFR <45 mL/min/1.73/m² even with no proteinuria or any other co-morbidity.

o   eGFR <45 mL/min/1.73 m² + proteinuria + DM or other co-morbidities &

o   eGFR <30 mL/min/1.73 m² considered at highest risk for all ptns.

 

Preventive measures:

[1] Avoid volume depletion & NSAIDs: ptns receiving intra-arterial contrast should avoid dehydration and volume depletion. Withhold NSAIDs 24-48 h.s prior to the study. Both volume depletion & NSAIDs can augment renal VC that trigger the risk of CI-AKI. No withhold ACEi & ARBs is advised. Data are insufficient to assure a benefit of ACEi/ARBs withdrawal and there is risk with resultant HT.

[2] Dose & type of contrast agent: administration of the lowest effective possible dosing of contrast is advised with avoiding repeated close procedures (48-72 hs). Iso-osmolal agent, iodixanol, or non-ionic low-osmolal media, e.g. iopamidol or ioversol, rather than iohexol. Do not inject high-osmolal media (1400-1800 mosmol/kg). Non-ionic, iso- or low-osmolal media are safer than ionic high-osmolal media. The iso-osmolal, iodixanol, may be safer than iohexol among risky ptns but shows only a slight, if any, benefit compared to other non-ionic low-osmolal media. The 2012 KDIGO guidelines recommended low-osmolal or iso-osmolal rather than higher-osmolal media but they found no real supporting evidence to recommend either low- vs iso-osmolal contrast.

[3] Fluids:  ALL at-risk ptns proceeding to intra-arterial contrast, if no C.I. to volume expansion > IV isotonic Saline before to & several h.s after the contrast study.

A preferred protocol is following:

o   Outptns: 3 mL/kg over one h. prior to the procedure and 1-1.5 mL/kg/h during and for 4-6 h.s after procedure, at least 6 mL/kg post-contrast.

o   In-ptns: 1 mL/kg/h. for 6 -12 h. pre-contrast, intra-contrast, and for 6-12 h.s after the procedure.

o   Rationale: IV volume expansion prior to procedure for high risk ptns is the standard care despite lack of RCT. Further trials comparing prox fluids to no fluid are needed. Few RCT tested effects of IV fluids with no other interventions (e.g., forced diuresis). 3 RCT showed benefit, but of limited values:

2 trials: 408 & 216 ptns with AMI performing PCI, with mostly normal renal profile, IV  Sln decreased the risk of CI-AKI as compared to no Sln. Trial: in-hospital MR was lowered with IV Sln (2.8 vs 9.3 %). Rates of ventricular arrhythmias, APO, DX, mechanical ventilation were lower in ptns receiving Sln. However, in both trials, prevalence of AKI that decreased with fluid, may have been attributed to limitation in episodic hypotension via IV hydration rather than a direct protective anti-CI-AKI impact on high-risk ptns.

Non-placebo-controlled RCT (POSEIDON) showed indirect evidence of a beneficial dose-response of fluid optimization. An aggressive fluid hydration protocol guided by LVEDP was compared to standard IV fluid, eGFR <60 mL/min/1.73 m². All ptns received IV isotonic Sln 3 mL/kg for one h. before cardiac catheterization. LVEDP was assessed in all ptns prior to contrast. In the LVEDP-guided g., ptns received:

o   5 mL/kg/h if LVEDP = < 13 mmHg,

o   3 mL/Kg/h if LVEDP = 13-18 mmHg, &

o   1.5 mL/Kg/h. if LVEDP = > 18 mmHg.

o   The control g. received 1.5 mL/kg/h.

Both g.s received IV fluid throughout the procedure & 4 h.s afterward. CI-AKI observed less frequently in the LVEDP g. as compared to control.    

Isotonic saline: Isotonic Sln appears to be better than more hypotonic fluids (i.e., 1/2 isotonic saline). RCT: 1620 ptns, compared with 1/2 -isotonic Sln, isotonic Sln decreased the risk of CI-AKI. Impact of isotonic saline was higher in Dcs (5.5 % vs 0) & ptns given >250 mL of contrast media (3 vs 0 %). However, there was no observed difference with significant renal impairment (SCr >1.6 mg/dL [>141 micromol/L]). It is vital limitation as ptns with RI who will be at higher risk for CI-AKI, this trial was underpowered in the item of sub-g.; so, a minimal benefit of Sln may have been missing here.

Saline vs bicarbonate: We recommend Sln rather than bicarbonate. Both are effective, but Na⁺HCO₃ gives no more benefit to Sln, with the need to be compounded, and is more costly. Na⁺HCO₃ has been compared with isotonic Sln in a number of RCT & meta-analyses with conflicting data. The most informative RCT: 4993 high-risk ptns with planned angio-study: both therapies showed similar outcomes. All ptns with stable renal function, eGFR 15-44.9 mL/min/1.73 m² with or without DM or eGFR 45-59.9 mL/min with DM. 81% were diabetics. Ptns received 1.26 % Na⁺HCO3 or 0.9 % Na⁺ Cl + either oral AC (1200 mg one h. before & one h. after angio, then twice/d./4 d.) or placebo capsules. Hydration was as follows of 1-3 mL/kg/h/1-12h before angio (total 3-12 mL/kg), 1-1.5 mL/kg/h. during angio & 3 mL/kg/h./2-12 h. after angio (total 6-12 mL/kg after angio). Similar rates of AKI, need for DX at 90 d.s or persistent RI by 90 d.s & death rate in Na⁺HCO₃ & Sln g.  

Oral salt loading: We do not use oral salt loading in place of IV volume expansion. The benefit of oral hydration or salt loading for the prevention of CI-AKI is not known. However, 2 small trials have suggested that oral salt may provide a benefit comparable with IV fluids.

Acetylcysteine (AC): AC not given prior to angio. Meta-analyses: AC have shown variable results. Generally, moderate benefits were observed in meta-analyses. The largest RCT, did NOT show better outcome with oral AC in 4993 high-risk ptns with planned angio. Benefit of IV AC still uncertain, one trial: 7 % of ptns receiving high dosages IV AC experienced anaphylactoid reaction.

UNPROVED AGENTS: RIPC, ANP, statins, & Aa.

Remote ischemic pre-conditioning: RIPC is a method by which the deliberate induction of transient non-lethal ischemia of an organ protects against subsequent ischemic injury of another organ. Some, but not all, studies have suggested that RIPC prior to cardiac surgery protects against AKI.  RIPC may also protect against CI-AKI. These data need to be confirmed in larger RCT before RIPC can be advised as a preventive measure for CI-AKI.

Prox hemofiltration & HDX: Routine HF/HDX for CI-AKI prevention in CKD is not advised.  A 2012 meta-analysis including 8 studies of HDX & 3 studies of HF/HDF showed No benefit of RRT. There’s no indication for prox DX to prevent volume overload related to IV contrast in DX-dependent ptns.

Furthermore, there are no studies supporting immediate DX after intravascular contrast studies to preserve residual kidney function or to limit the risk of allergic or toxic reactions to contrast media in HDX ptns. Whereas some clinicians try to perform a HDX within 24-36 h.s after intravascular contrast media exposure, others wait 48-72 hs, until the next scheduled HDX. The latter approach is advised, except in HDX ptns who are significantly volume overloaded at the time of contrast study. Withholding ACEi/ARBs prior to angio-study is not recommended. Some studies have suggested that ptns on an ACEi/ARBs are at higher risk for CI-AKI as compared to ptns who are not.

However, it is not clear whether holding or withdrawing an ACEi and/or ARB prior to angio-studies provides any benefit. Study: 220 ptns who were on ACEi or ARBs with an eGFR of 15-59 mL/min/1.73 m² were assigned before angiography to either an ACEI/ARB withdrawal g., in which ACEi/ARB were stopped 24 h. before the procedure, or to a control g., in which ACEi/ARB were continued. There was no significant difference in the incidence of CI-AKI between ptns having ACEi/ARB withdrawn and those who did not. The issue of whether to hold ACEi/ARBs prior to contrast study is not resolved, and further studies have been required.

Statins: statins administration totally not advised for the prevention of CI-AKI. A possible exception is ptns who are likely to be started on statins prior to discharge, such as those with AMI, among whom it’s reasonable to start statin prior to angiography.

Some studies suggested: statins may reduce the risk. A meta-analysis of 8 studies (n = 5024) did not show a conclusive benefit of statins plus IV Sln compared with Sln alone. However, analysis of 5 studies (n = 1477) revealed that statins given with AC & IV Sln reduced the risk of CI-AKI compared with AC & IV Sln alone. Most of the statin studies were performed in relatively low-risk ptns. Moreover, some reports suggest that acute administration of rosuvastatin is associated with a rise in normal eGFR. Statins desrve more workup for CIN prophylaxis.

Diuretics: routine prox diuretics or mannitol for prevention of AKI is not advised. These medications seem to be not beneficial for CI-AKI prox. However, diuretics may be provided to manage volume overload.

It’s possible that forced diuresis can help in AKI prevention if volume depletion can be prevented as shown in studies utilizing the proprietary of fluid control devices matching fluid repletion to UO. Forced diuresis + matched volume replacement can decline the possibility of AKI after angiography as compared to overnight hydration.  The potential benefit of the fluid managing devices is that volume repletion & UO are hourly controlled more than the conventional hydration protocols with no added risk of volume overload. On the other hand, forced diuresis of high-volume has its sequelae, even with application of the well-matched volume repletion. Volume overload may be developed if isotonic Sln have been administrated to replace urine that is after loop diuretics, usually of tonicity of ½ normal Sln.

One trial: the raised intravascular volume may be sufficient to augment the eGFR in ptns commencing forced diuresis. Moreover, forced diuresis may precipitate arrhythmia via electrolyte alterations e.g., hypokalemia can be complicated in susceptible ptns.

Others: oral Na⁺ citrate, ANP, Aa, trimetazidine, VC inhibitors, and diuretics:

o   Oral Na⁺ citrate: One RCT:  benefit of oral Na⁺ citrate (5 g/200 mL water) one h. before & 4 hs after angio-study. Risk of CI-AKI was lowered with ptns receiving oral citrate as compared to placebo (need to be confirmed).

o   ANP (anaritide): beneficial in animals, but NOT in humans- for CI-AKI prox.

o   Ascorbic acid (Aa): Data are sparse about Aa for CI-AKI prox. One RCT:  proved benefit of Aa in CIN prox, but another larger trial: No added benefit to a prox isotonic Sln + Aa: in risky ptns. Meta-analysis: 6 trials: No benefit of Aa.

o   Trimetazidine: cellular anti-ischemic agent additional protection to isotonic Sln from CI-AKI in a small, prospective trial. Further work up is warranted.

o   VC Inhibitors: Many agents preventing VC, e.g., theophylline/aminophylline, captopril, PG E, low-dose dopamine, & fenoldopam, have been tried for CI-AKI prox, some but not all, trial prove risk reduction.  

PROGNOSIS CI-AKI is mostly reversible; eGFR may recover in 5-10 days. However, risky ptns with severe basal decline in eGFR, the SCr may NOT recover to its previous baseline. Even if SCr returned to baseline, the evolution of CI-AKI can be associated with short- & long-term untoward impacts.  However, there’re NO current RCT with proved specific interventions preventing AKI, decreasing MR or protecting from the expected serious CVS events.