Contrast-associated acute kidney injury (CA-AKI) is a complication of procedures requiring intravascular administration of iodinated contrast media1–3 and its risk depends on patient- and procedure-related factors.4 The strongest independent patient- and procedure-related predictors of CA-AKI are chronic kidney disease and use of high volumes of contrast medium, respectively.5–8 Strategies for CA-AKI prevention so far have focused on intravascular volume expansion (eg, by periprocedural use of isotonic saline, half-isotonic saline, isotonic sodium bicarbonate), pharmaceutical agents (eg, acetylcysteine, statins), and renal replacement therapies. Although several observational studies and randomized controlled trials have been published, there is no robust evidence of benefit with these interventions.9–13 Current guidelines recommend administering periprocedural intravenous fluids and minimizing the amount of contrast medium as the primary interventions to mitigate the risk of CA-AKI.14

RenalGuard (PLC Medical Systems, United States) is a system engineered to ensure adequate hydration while providing contrast medium clearance; the system delivers real-time isotonic intravenous hydration matched with high urine output induced by furosemide in the attempt to prevent conditions of either hyper- or hypovolemia.15 To date, RenalGuard has been tested in a few small randomized trials with low power to detect differences in major clinical endpoints and high variability in patient characteristics and procedures.16–21 Meta-analyses of RenalGuard are available but their conclusions are limited by the inclusion of observational studies. In addition, these meta-analyses mostly used frequentist models, which are limited when accounting for between-trial variability or if there are low event rates.22–24 Finally, a new trial of RenalGuard has been made available that was not included in the previous meta-analyses.21

Against this background, we used a Bayesian framework to perform a meta-analysis of RenalGuard as a CA-AKI preventive strategy for patients undergoing percutaneous cardiovascular procedures to a) increase the statistical power of individual trials for assessing infrequent outcomes; b) avoid the methodological limitations of previous frequentist meta-analyses; and c) update prior meta-analyses based on the most recent evidence available.

In this Bayesian meta-analysis, the RenalGuard system was associated with a reduced risk of CA-AKI and acute pulmonary edema, with no difference in all-cause mortality, cardiogenic shock, or acute renal failure requiring renal replacement therapy compared with standard periprocedural intravenous hydration. These results were replicated in several sensitivity analyses, highlighting a valuable role of the RenalGuard system in reducing the incidence of kidney injury after cardiovascular procedures requiring the administration of large amounts of contrast media. Importantly, this outcome was obtained while limiting and even improving the potential consequences of uncontrolled hydration strategies (ie, volume overload and acute pulmonary edema). By means of the Bayesian approach, we were able to show a 95% probability of the RenalGuard system being superior to the control arm in reducing the risk of CA-AKI.

Hydration and minimization of contrast media are essential strategies in CA-AKI prevention.9–14 Tailoring the hydration regimen has been suggested as an alternative to conventional hydration; however, despite several trials and observational registries that have assessed this approach by using the RenalGuard system, the supporting evidence remains scarce and does not allow for definitive conclusions. In particular, the variability of patients included in clinical trials (eg, due to lack of criteria for the selection of the best candidates for the RenalGuard system) resulted in a low-grade level of evidence. Based on this background, our objective was to summarize the most contemporary evidence from the available randomized trials of the RenalGuard system while overcoming some known limitations of frequentist meta-analyses, including their poor ability to estimate pooled treatment effects if there were low event rates due to the use of continuity correction models27 and their overreliance on P values, which do not represent the actual direct probability of response to the treatment.28 Importantly, compared with the previously published meta-analyses, our study focuses on the direct comparison of the RenalGuard system with standard hydration strategies, and adds incremental information by inclusion of the most recent evidence on the topic and avoidance of the variability (ie, “noise”) introduced by indirect comparisons.29 Moreover, the use of random-effects rather than fixed-effects models allowed us to limit the influence of between-trial variability and biological differences on the overall results. We also included a trial sequential analysis, which was not available in other meta-analyses, suggesting that the information size gathered so far in the available randomized trials is sufficient to claim this result to be conclusive.

Although the precise mode of action of the RenalGuard system is not well understood, the high urine output achieved by means of properly matched intravenous hydration in our meta-analysis translated into a significant 46% decrease in the relative risk of CA-AKI. This result is consistent with those of previous studies23,24 and is also in line with several histopathological findings indicating medullary hypoxia as a cause of renal damage through tubular cell injury.30,31 Assuming that volume depletion as a risk factor for renal hypoxia, it can be speculated that achieving a good balance between renal perfusion and proper diuresis has a direct protective effect on the tubular cells, minimizing the risk of injury.32

All our prespecified sensitivity analyses based on varying definitions, timing of assessment (ie, increase of plasma creatinine levels within 48hours from the procedure) and/or diagnostic cutoffs (ie, increase in plasma creatinine levels> 0.5mg/dL) favored, at least directionally, the RenalGuard system. Interestingly, the treatment effect was even higher after exclusion of trials of transcatheter aortic valve implantation, which might be attributed to positive hemodynamic effects after the procedure (ie, due to afterload reduction resulting in improved inotropic cardiac performance) that oppose medullary hypoxia and tubular cell damage, thus downsizing the relative impact of the RenalGuard system.33

Although, from a cost-effectiveness standpoint, the reduction in CA-AKI appears to be attractive,34 it should be acknowledged that the RenalGuard system could represents a potentially costly intervention. A cruder and cheaper approach has recently been tested, based on the idea that an aggressive hydration protocol guided by invasive left ventricle pressure measurements could be beneficial in preventing CA-AKI. However, when compared with standard hydration protocols, the results were controversial.35,36 Moreover, to date, no studies have directly compared RenalGuard with this strategy, and some issues remain unsolved. In particular, because of the requirement for invasive left ventricular pressure measurements to define the fluid rate, the preventive measure can be started only shortly before contrast media administration, neutralizing the potential benefits of more extensive preprocedural hydration. Moreover, as reported in the POSEIDON trial,37 this approach translated into greater fluid administration compared with the standard strategy. These issues, together with the lack of diuresis-matched tracking and with postprocedural pressure measurements, raised some concerns over the application and future of hydration guided by invasive left ventricular pressure measurements as a CA-AKI prevention measure.

Importantly, the benefit of the RenalGuard system did not come at the expense of safety. No difference was observed in the risk of all-cause mortality or cardiogenic shock, and there was even a 65% decrease in the relative risk of acute pulmonary edema. The strong protective association between the RenalGuard system and acute pulmonary edema is an unexpected novel finding with notable implications.23 Indeed, acute pulmonary edema inevitably impacts on patient management and prognosis, particularly when its occurrence is incorrectly attributed to acute pump failure rather than uncontrolled fluid overload, which may lead to useless and even harmful downstream investigations. The beneficial effect of acute pulmonary edema reduction in the investigational group may depend on the use of furosemide, an effect mediated by the blockage of tubular sodium reabsorption in the loop of Henle, which decreases the tubular workload. This effect could lead clinicians to consider furosemide administration alone as a way to prevent acute pulmonary edema. Nevertheless, using furosemide with no adequate matching hydration decreases the effective circulating volume and prostaglandin mediated vasodilation, potentially resulting in dehydration and increasing the risk of tubular damage,38 thus reinforcing the evidence and suggesting a valuable synergic effect of real-time isotonic intravenous hydration matched with high urine output provided by RenalGuard use.

The trial sequential analysis indicated that the information size gathered so far in the available randomized trials is sufficient to claim this result as conclusive. In contrast, we found no differences with the RenalGuard system in reducing renal failure requiring renal replacement therapy. This results is at odds with those of previous meta-analyses showing a lower need for renal replacement therapy, possibly as a result of including heterogenous treatment strategies in the control arm with a low number of events.22,23,39

When discussing the external validity of our results and their real applicability in clinical practice, it is important to point out that all the studies incorporated in our analysis included patients with chronic kidney disease or considered at high-risk for the condition. Therefore, our results demonstrated consistent beneficial effects of RenalGuard use in patients with a high-risk profile. This reinforces the importance of accurate risk stratification and clinical selection to achieve the best result and reduce medical costs.

In patients undergoing percutaneous cardiovascular procedures, the use of the RenalGuard system was associated with a reduced incidence of CA-AKI and acute pulmonary edema. These positive effects did not come at the expense of increased mortality or cardiogenic shock.

None.

G. Occhipinti conceived the study and drafted the manuscript; C. Laudani performed the statistical analysis; M. Spagnolo participated in the design of the study; A. Greco participated in the design of the study and reviewed the manuscript; D. Capodanno reviewed the manuscript for intellectual content, and supervised and validated the study. All authors read and approved the final manuscript.

None.