KDIGO Clinical Practice Guideline for Acute Kidney Injury
Fluid Administration: Recommendations and Rationale

Chapter 4.4: Pharmacological prevention strategies of CI-AKI

Fluid administration

Extracellular volume expansion at the time of radiocontrastmedia administration may serve to counteract both the intrarenal hemodynamic alterations and the direct tubulotoxic effects that play a role in the pathophysiology of CIAKI. Neurohumoral effects of volume expansion that may attenuate radiocontrast-induced medullary hypoxia include suppression of vasopressin as well as inhibition of the reninangiotensin axis; but an increased synthesis of vasodilatory renal prostaglandins may also play a role.⁴⁶⁴

Volume expansion may also directly reduce cellular damage by dilution of the contrast medium, particularly in the medullary tubular segments. Likewise, an effect of radiocontrast media to increase tubular fluid viscosity may be diminished by intravascular volume expansion.⁴⁶⁵ It is important to note that these potentially attenuating effects of volume expansion are speculative, and the precise mechanisms by which volume expansion protects against CI-AKI remain unknown.

• 4.4.1: We recommend i.v. volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions, rather than no i.v. volume expansion, in patients at increased risk for CI-AKI. (1A)

Rationale

Despite the recognition of volume depletion as an important risk factor for AKI, there are no RCTs that have directly evaluated the role of fluids vs. placebo in the prevention of AKI. However, RCTs have compared different fluids and have combined fluids with other interventions.¹⁹¹ Furthermore, comparisons between outcomes seen in these trials¹⁹¹ and historical untreated control subjects⁴⁶⁶ suggest a large benefit from fluids. In particular, volume expansion and treatment of dehydration are well-established interventions in the prevention of CI-AKI. A recent propensity analysis, however, noted that strategies to prevent CI-AKI are implemented rather nonuniformly.⁴⁶⁷ Pre– and post–contrast-media administration i.v. fluids were given to only 264 of 660 study patients (40.0%), more commonly with coronary angiography than with CT (91.2% vs. 16.6%). Other preventive measures, such as administration of NAC or discontinuation of NSAIDs, were equally rarely applied. Only 39.2% of patients received NAC, while only 6.8% of patients were instructed to discontinue NSAIDs. In a propensity analysis, the use of i.v. fluids was associated with a reduced rate of CI-AKI. The incidence of CI-AKI was lowest following CT (range, 0.0–10.9%) and was highest following noncoronary angiography (range, 1.9–34.0%).

The fluids that have been tested in the prevention of CI-AKI are hypotonic saline (0.45%), isotonic saline (0.9%) and isotonic sodium bicarbonate. The interpretation of all these studies is hampered by the fact that not all other risk factors (susceptibilities) for CI-AKI were excluded or considered in every study (i.e., age of the patient, presence of CKD and/or diabetes prior to contrast-media administration, type and dose of contrast agent, associated therapy with NAC, and other risk factors [see Chapter 2.2]).

There is no clear evidence from the literature to guide the choice of the optimal rate and duration of fluid infusion in CI-AKI prevention, but most studies suggest that the fluids should be started at least 1 h before and continued for 3–6 hours after contrast-media administration. A ‘‘good’’ urine output ( > 150 ml/h) in the 6 hours after the radiological procedure has been associated with reduced rates of AKI in one study.⁴⁶⁸ Since not all of i.v. administered isotonic crystalloid remains in the vascular space, in order to achieve a urine flow rate of at least 150 ml/h, ≥ 1.0–1.5 ml/kg/h of i.v. fluid has to be administered for 3–12 hours before and 6–12 hours after contrast-media exposure.

Mueller et al.⁴⁶⁹ found that i.v. 0.9% saline solution, compared to 0.45% saline solution in dextrose, in 1620 patients undergoing coronary angiography significantly reduced CI-AKI. The sustained administration of isotonic saline before and after radiocontrast injection seems, thus, to be more protective than equivalent volumes of hypotonic saline.⁴⁶⁴ Although the mechanism by which sodium bicarbonate, beyond its volume-expanding effects, might further reduce CI-AKI remains poorly defined, it has been postulated that sodium bicarbonate infusion may decrease generation of free radicals mediated by the Haber-Weiss reaction by increasing tubular pH. The Haber-Weiss reaction is most active at lower pH levels.⁴⁷⁰ Sodium bicarbonate infusion may also scavenge the potent oxidant peroxynitrate, produced via a nitric oxide–mediated pathway.⁴⁷¹ Reactive oxygen species activate cytokine-induced inflammatory mediators, resulting in damage to proximal tubular cells,⁴⁷² and it is likely that the activation of these mediators is influenced by tissue hypoxia and intracellular medullary acidosis.⁴⁷³

It is worth noting that, compared to i.v. bicarbonate, the combination of oral azetazolamide inducing an alkaline urine, plus i.v. saline, was more effective for the prevention of

Figure 15 | Bicarbonate vs. saline and risk of CI-AKI. Reprinted from Zoungas S, Ninomiya T, Huxley R et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med 2009; 151: 631–638 with permission from American College of Physicians⁴⁸¹; accessed http://www.annals.org/content/151/9/631.full

CI-AKI than saline alone, in a relatively small study in children with stable chronic renal failure (CRF).⁴⁷⁴ It could also be hypothesized that sodium bicarbonate has a stronger impact in lowering the intratubular viscosity caused by the contrast medium, compared to isotonic saline, because it causes less tubular sodium reabsorption than saline.

Sodium bicarbonate solutions have been tested in the prevention of CI-AKI in comparison with isotonic saline, either with or without NAC. A number of systematic reviews on the role of sodium bicarbonate compared to isotonic saline in the prevention of CI-AKI are available.^475–481

The most recent and probably the most complete systematic review⁴⁸¹ analyzed MEDLINE, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from 1950 to December 2008; conference proceedings; and ClinicalTrials.gov, without language restriction (Figure 15). This systematic review included RCTs of i.v. sodium bicarbonate that prespecified the outcome of CI-AKI as a 25% increase in baseline SCr concentration or an absolute increase of 0.5 mg/dl (44.2 µmol/l) after contrast-media administration. Twenty-three published and unpublished trials with information on 3563 patients and 396 CI-AKI events were included. The pooled RR was 0.62 (95% CI 0.45–0.86), with evidence of significant heterogeneity across studies. Some heterogeneity was due to the difference in the estimates between published and unpublished studies: RR 0.43 (95% CI 0.25–0.75) vs. 0.78 (95% CI 0.52–1.17), respectively. Meta-regression showed that small, poor-quality studies that assessed outcomes soon after contrast-media administration were more likely to suggest the benefit of bicarbonate (P < 0.05 for all). No clear effects of treatment on the risk for dialysis, heart failure, and total mortality were identified.

Suppl Tables 22 and 23 summarize the evidence from RCTs where isotonic bicarbonate was compared to isotonic saline alone, without concomitant other ‘‘preventive’’ interventions. In all studies, a minimum of 50 patients in both arms and publication as full paper were required for inclusion in the tables. Only three studies directly compared isotonic bicarbonate to isotonic saline.^470,482,483 In a fourth study by Brar et al.,⁴⁸⁴ NAC was included in 47% and 46% of the patients in both arms of the study (bicarbonate vs. saline), respectively. The first study was a small single-center RCT⁴⁷⁰ enrolling 119 patients with stable SCr of at least 1.1 mg/dl (97.2 µmol/l), randomized to either infusion of isotonic saline or isotonic sodium bicarbonate before and after contrast-media administration. CI-AKI (defined as an increase of 25% in SCr from baseline within 48 hours) developed in 1.7% in the bicarbonate group, compared to 13.6% in the saline solution group.

Ozcan et al.⁴⁸³ included three prophylactic regimens: infusion of sodium bicarbonate, sodium chloride, and sodium chloride plus oral NAC (600mg b.i.d.). The incidence of CI-AKI, defined as an increase in SCr level > 25% or 0.5mg/dl (44.2 µmol/l) after 48 hours was significantly lower in the sodium bicarbonate group (4.5%) compared to sodium chloride alone (13.6%, P = 0.036). After adjusting for the Mehran nephropathy risk score, the risk of CI-AKI significantly reduced with sodium bicarbonate compared to sodium chloride alone (adjusted risk ratio 0.29; P = 0.043).

By contrast, Adolph et al.⁴⁸² did not find differences in CIAKI between the two fluid regimens on day 1 after angiography; even on day 2, most parameters were similar in both groups. In none of the above-mentioned studies was there need for RRT.

Finally, a recent but retrospective study⁴⁸⁵ defined CI-AKI as an increase in SCr ≥ 25% within 48 hours of receiving contrast media, and compared sodium bicarbonate to normal saline in patients exposed to cardiac angiography. One group of patients (n = 89) received prophylactic bicarbonate; a second group, normal saline (n = 98). The patients in the bicarbonate group had more severe renal disease with higher baseline SCr (1.58 ± 0.5 mg/dl; 140 ± 44.2 µmol/l) vs. (1.28 ± 0.3 mg/dl; 113 ± 26.5 µmol/l), P = 0.001 and a lower eGFR, compared to the normal saline group. After contrast-media exposure, there was significant drop in eGFR (6.4%) and increase in SCr (11.3%) in the normal saline group and no significant change in the bicarbonate group. Three patients (3.4%) in the bicarbonate group, as opposed to 14 patients (14.3%) in the normal saline group, developed CI-AKI (P = 0.011). Two patients in the normal saline group and none in the bicarbonate group needed dialysis. This study suggests that the use of i.v. sodium bicarbonate is more effective than normal saline in preventing CI-AKI.

Three studies compared bicarbonate and saline solutions associated with the administration of NAC in both study arms.^486-488 Recio-Mayoral et al.⁴⁸⁸ conducted a prospective single-center RCT in 111 consecutive patients with acute coronary syndrome undergoing emergency angioplasty. One group of patients received an infusion of sodium bicarbonate plus NAC started just before contrast-media injection and continued for 12 hours after angioplasty. The second (control) group received the standard fluid protocol consisting of i.v. isotonic saline for 12 hours after angioplasty. In both groups, two doses of oral NAC were administered the next day. A SCr concentration > 0.5 mg/dl ( > 44.2 µmol/l) from baseline after emergency angioplasty was observed in 1.8% in the bicarbonate group and in 21.8% of the saline group. Mortality and need for RRT were not significantly different between both groups. Briguori et al.⁴⁸⁶ randomized 326 CKD patients (SCr ≥ 2 mg/dl [ ≥ 177 µmol/l] and/or eGFR < 40 ml/min per 1.73 m²), and referred for coronary and/or peripheral procedures to three different protocols: prophylactic administration of 0.9% saline infusion plus NAC (n = 111), sodium bicarbonate infusion plus NAC (n = 108), and 0.9% saline plus ascorbic acid plus NAC (n = 107). CI-AKI was defined as an increase of ≥ 25% in the SCr concentration 48 hours after the procedure. CI-AKI occurred in 9.9% of the saline plus NAC group, in 1.9% of the bicarbonate/NAC group (P = 0.019 vs. saline plus NAC group), and in 10.3% of the saline plus ascorbic acid plus NAC group (P = 1.00 vs. saline plus NAC group). There was no difference in mortality nor in need for RRT among the different groups. While these two studies suggest that isotonic bicarbonate may provide greater benefit than isotonic saline, either in association with NAC or not, neither study can be considered conclusive.

Maioli et al.⁴⁸⁷ prospectively compared the efficacy of sodium bicarbonate vs. isotonic saline in addition to NAC in a larger population of 502 patients with an estimated CrCl < 60 ml/min, and undergoing coronary angiography or intervention. CI-AKI was defined as an absolute increase of SCr ≥ 0.5 mg/dl ( ≥ 44.2 µmol/l) measured within 5 days. CIAKI occurred in 10.8%; 10% were treated with sodium bicarbonate and 11.5% with saline. In patients with CI-AKI, the mean increase in creatinine was not significantly different in the two study groups. Based on this last prospective study, bicarbonate does not seem to be more efficient than saline. Furthermore, a retrospective cohort study at the Mayo Clinic assessed the risk of CI-AKI associated with the use of sodium bicarbonate, NAC, or the combination. Surprisingly, i.v. sodium bicarbonate was associated with an increased incidence of CI-AKI.⁴⁸⁹

While one might take the position that, if in doubt, one should choose the regimen that is potentially superior, the Work Group also considered the potential harm. In addition, isotonic bicarbonate solutions are usually composed by adding 154 ml of 8.4% sodium bicarbonate (i.e., 1 mmol/ ml) to 846 ml of 5% glucose solution, resulting in a final sodium and bicarbonate concentration of 154 mmol/l each. Since this mixing of the solution is often done at the bedside or in the hospital pharmacy, there is the possibility for errors leading to the infusion of a hypertonic bicarbonate solution. The potential for harm from dosing errors, and the added burden from preparation of the bicarbonate solution, has to be taken into account in clinical practice when making a choice between using bicarbonate rather than standard isotonic saline solutions. Taken together, the Work Group concluded that there is a possible but inconsistent benefit of bicarbonate solutions based on overall moderate-quality evidence (Suppl Table 22). As discussed above, the potential of harm and the additional burden for preparing the bicarbonate solutions led the Work Group not to express a preference for or against one solution (isotonic saline or isotonic bicarbonate). Thus, either can be used for the prevention of CI-AKI.