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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 1  |  Issue : 2  |  Page : 61-68

The Intensity of Renal Replacement Treatment for Acute Kidney Injury: A Systematic Review and Network Meta-Analysis


1 Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
2 Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China

Date of Submission19-Jun-2019
Date of Acceptance28-Aug-2019
Date of Web Publication27-Sep-2019

Correspondence Address:
Prof. Kaijiang Yu
Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, No. 150, Haping Rd., Nangang District, Harbin 150081
China
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DOI: 10.4103/jtccm.jtccm_11_19

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  Abstract 


Background: Acute kidney injury (AKI) is a common and serious complication in critically ill patients. Patients who require renal replacement therapy (RRT) face a high mortality rate. Questions concerning the intensity of RRT in AKI patients led us to integrate direct and indirect evidence using a network meta-analysis to determine the optimal intensity and mode. Materials and Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Web of Science databases from 1990 to 2017 that included randomized controlled trials (RCTs) comparing different intensities of RRT to treat AKI in adults (18 years or older). Data regarding study characteristics, methods, and outcomes were extracted. We assessed the studies for eligibility, extracted the data, pooled the data, and used the GeMTC package in R to combine direct comparisons with indirect evidence. Results: Ten RCTs including 3354 participants were included in the network meta-analysis. The higher intensity continuous renal replacement treatment (CRRT) (to exceed 35 mL/kg/h) and the higher intensity IRRT (to exceed six times per week) both showed no statistical significance. Further analysis for higher intensity CRRT, lower intensity CRRT, higher intensity IRRT, and lower intensity IRRT also revealed no significance. Conclusions: This meta-analysis showed that increasing the intensity of CRRT to exceed 35 mL/kg/h and six times per week for intermittent RRT (IRRT) did not reduce mortality or the rate of dependence on dialysis among AKI patients.

Keywords: Acute kidney injury, meta-analysis, mortality rate, renal replacement treatment


How to cite this article:
Wang H, Liu H, Wang Y, Tong H, Yu P, Chen S, Wang G, Liu M, Li Y, Guo N, Wang C, Yu K. The Intensity of Renal Replacement Treatment for Acute Kidney Injury: A Systematic Review and Network Meta-Analysis. J Transl Crit Care Med 2019;1:61-8

How to cite this URL:
Wang H, Liu H, Wang Y, Tong H, Yu P, Chen S, Wang G, Liu M, Li Y, Guo N, Wang C, Yu K. The Intensity of Renal Replacement Treatment for Acute Kidney Injury: A Systematic Review and Network Meta-Analysis. J Transl Crit Care Med [serial online] 2019 [cited 2021 May 14];1:61-8. Available from: http://www.tccmjournal.com/text.asp?2019/1/2/61/268083




  Introduction Top


Acute kidney injury (AKI), formerly known as acute renal failure (ARF), is a common and serious complication among critically ill patients.[1],[2] A recent multinational, multicentric study of 1738 critically ill patients with AKI revealed that the in-hospital mortality is high, exceeding 60%.[3] In patients with severe AKI, renal replacement therapy (RRT) represents a cornerstone of treatment. Although medical care has improved, critically ill patients with AKI who require RRT still face a high mortality rate >50%.[3] Although there has been great development in this area, many problems remain still unanswered.[4] The optimal timing for the initiation, method, and dosing of RRT remain uncertain more than 60 years after the first clinical use of hemodialysis (HD) in patients with AKI.[5],[6],[7] Whether more intensive RRT improves the outcomes of patients with AKI is an ongoing debate. Several studies have reported benefits associated with more frequent dialyses and/or higher-dose regimens; for example, Schiffl et al. compared 160 patients with ARF assigned to receive daily or conventional intermittent HD (IHD) and found that intensive HD can reduce mortality without increasing the incidence of hemodynamic adverse events.[8] Another randomized trial regarding continuous veno-venous hemofiltration (CVVH) also showed the benefit of more intensive RRT,[9] whereas other studies have reported no such benefit. Tolwani et al. compared standard versus high-dose continuous veno-venous hemodiafiltration (CVVHDF) for intensive care unit (ICU)-related ARF and found no difference in patient survival or renal recovery between patients receiving high-dosage or standard-dosage CVVHDF.[10] Similarly, Palevsky et al. randomly assigned 1124 critically ill patients with AKI to receive an intensive treatment strategy or a less intensive treatment strategy. They found that intensive renal support did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure.[11] Zhang et al. extracted data from six randomized controlled trials (RCTs) to perform a meta-analysis; they found that a higher dose of continuous renal replacement treatment (CRRT) was not sufficient to reduce mortality in critically ill patients with ARF.[12] Based on the above results, whether the intensity of RRT for AKI can affect the outcomes is still controversial. RRT modes include CRRT and intermittent renal replacement treatment (IRRT). CRRT includes many types of patterns such as CVVH, CAVH, CVVHDF, and continuous veno-venous HD. IRRT includes IHD, intermittent hemodiafiltration, and slow low-efficiency dialysis (SLED).

The aim of the present study was to investigate the effect of the intensity of RRT. We employed a meta-analysis that included RCTs examining different modes of RRT for AKI patients to compare higher intensity RRT with lower intensity RRT. We also employed a network meta-analysis of RCTs to compare higher intensity CRRT, lower intensity CRRT, higher intensity IRRT, and lower intensity IRRT to determine the optimal intensity and approach to RRT.


  Materials and Methods Top


Search strategy and selection criteria

We conducted our systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.[13]

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Web of Science databases using a combination of MeSH terms and keywords relevant to RRT, AKI, adults, and RCTs [Supplement 1][Additional file 1]. The language or year of publication was not restricted in our search. The most recent search update was conducted in May 2017. We also reviewed the reference lists of the published meta-analyses. In addition, we manually searched the Index Medicus for RCTs, meta-analyses, and systematic reviews that were missed by the initial electronic search.

RCTs were included. Reviews, retrospective studies, observational studies, case reports, experimental studies of children, animal studies, irrelevant studies, and low-quality studies were excluded. Patients who were critically ill adults (18 years or older) with a primary diagnosis of AKI clinically consistent with acute tubular necrosis and requiring RRT were eligible for inclusion. Patients who received any previous RRT during the same hospital admission or who were on maintenance dialysis for end-stage kidney disease were ineligible for the study.

Data analysis

Two reviewers (YW and HST) independently reviewed the title/abstract of citations identified from the search strategies, obtained the full texts of potentially relevant studies, and then determined whether to include the studies using the same eligibility criteria. In addition, the references of relevant reviews and included trials were reexamined by the two reviewers. Any disagreements were resolved by a third review author (SSC).

Information was extracted from all eligible publications carefully and independently by two authors (YHL and PLY). The data extracted by a single author (NNG) were double-checked by a second author (ML or GYW), and discrepancies were resolved through discussion. The standardized data extraction forms included the trial characteristics (e.g., first author, year of publication, number of experimental centers, and country), patient characteristics (e.g., type of patients, number of patients, and age of the patients), and intervention details (e.g., pattern of RRT and intensity of RRT). The primary outcome was the short-term mortality, with a conclusion time of no more than 30 days. The secondary outcomes included the mid-term mortality, with a conclusion time between 30 and 60 days; long-term mortality, with a conclusion time of no less than 60 days; the renal recovery rate, which was defined as freedom from any RRT; length of ICU stay; and length of hospitalization.

Two review authors independently assessed the risk of bias in the included studies by considering the following characteristics: randomization sequence generation: was the allocation sequence adequately generated? Treatment allocation concealment: was the allocated treatment adequately concealed from the study participants, clinicians, and other health-care or research staff at the enrollment stage? Blinding: were the personnel assessing the outcomes and analyzing the data sufficiently blinded to the intervention allocation throughout the trial? Completeness of the outcome data: were the participant exclusion, attrition, and incomplete outcome data adequately addressed in the published report? Selective outcome reporting: was evidence of selective outcome reporting present and might this have affected the study results? Other sources of bias: was the trial apparently free of any other problems that could produce a high risk of bias? Disagreements between the review authors regarding the risk of bias in particular studies were resolved by discussion, with the involvement of a third review author when necessary.

Types of interventions

The higher intensity strategy involved CRRT of no less than 35 mL/kg of body weight per hour and IRRT of no less than six times per week. For the lower intensity strategy, the corresponding treatments were <35 mL/kg/h and less than six times weekly.

Statistical analysis

Statistical analysis was conducted using the GeMTC package in R (i386 3.0.2). Among the included studies, mortality was calculated by different time spans; therefore, to realize the maximum effectiveness and accuracy, hazard ratio (HR) values and 95% confidence intervals (CIs) were used as approximations to measure mortality in AKI patients. The model selection depended on the Dias guidelines for evaluating linear models.[14] A lower deviance information criterion value indicates a better model fit. The models were run for 150,000 iterations, and convergence was assessed using the Brooks–Gelman–Rubin diagnostic.[15] We used “back calculation”[16] to evaluate the consistency between direct and indirect sources of evidence. We assessed statistical heterogeneity with the I² statistic using the Higgins–Thompson method low heterogeneity, 25%; moderate heterogeneity, 50%; and high heterogeneity, 75%).[17] We also ranked the different interventions in terms of their likelihood of leading to an association with the best results for each outcome.[18]


  Results Top


A total of 9372 studies were identified for review in the initial screening; full text of 520 studies which proved potentially eligible were retrieved for a detailed assessment and 510 irrelevant studies were eventually excluded [Figure 1]. Ten RCTs [9],[10],[19],[20],[21],[22],[23],[24],[25],[26] assessed for eligibility were included in the meta-analysis, including 1937 patients who had a primary clinical diagnosis of AKI and required RRT [Table 1]. All studies were RCTs.
Figure 1: Flow diagram of literature search

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Table 1: Characteristics of the randomized controlled trials included for meta-analysis

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Heterogeneity

Among all included studies, seven reports were included in the network meta-analysis of the renal recovery rate, and all these studies were two-arm trials. In trials using higher intensive CRRT and lower intensive CRRT, for the short-term mortality end point, the I2 value exceeded 75% (I2 = 79%), indicating high heterogeneity. We reviewed the studies according to the data analysis and found that some patients in the study by Tolwani et al.[10] had preexisting chronic kidney disease and nephrotoxins, which may be a source of heterogeneity because renal recovery is influenced by these factors. Upon excluding this study, the remaining six articles [9],[19],[20],[21],[22],[23],[24],[25],[26] showed no heterogeneity [Supplement 2][Additional file 2].

Primary outcome

Short-term mortality

We first performed a meta-analysis to compare high-intensity and low-intensity RRT.

In terms of the short-term mortality, high-intensity RRT is superior to low-intensity RRT, although this was not statistically significant (random model: relative†risk (RR): 0.93, 95% CI: 0.82–1.06) [Figure 2]. In the network meta-analysis also [Figure 3], there was no statistical significance in the higher intensity CRRT compared to lower intensity IRRT (random model: HR: 0.94, 95% CI: 0.52–1.6), lower intensity CRRT compared to lower intensity IRRT (random model: HR: 1.08, 95% CI: 0.67–1.88), and higher intensity IRRT compared to lower intensity IRRT (random model: HR: 1.04, 95% CI: 0.59–1.67) [Figure 4].
Figure 2: The short-term mortality

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Figure 3: Network meta-analysis comparing the higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT

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Figure 4: The higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT revealed no statistical significance

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The probability ranking showed that higher intensity CRRT may result in lower short-term mortality than other modes of RRT [Supplements 3,4[Additional file 3][Additional file 4] and [Figure 5].
Figure 5: The probability ranking of the higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT

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Secondary outcomes

The secondary outcomes included the renal recovery rate, length of ICU stay, and length of hospitalization. After the meta-analysis and the network meta-analysis, the results of the comparison of high-intensity RRT and low-intensity RRT revealed no statistical significance [Supplements 5[Additional file 5] and [Figure 6], [Figure 7], [Figure 8].
Figure 6: The renal recovery rate of the comparison of high-intensity RRT and low-intensity RRT

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Figure 7: The length of intensive care unit stay of the comparison of high-intensity RRT and low-intensity RRT

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Figure 8: The length of hospitalization of the comparison of high-intensity RRT and low-intensity RRT

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The comparison of the higher intensity CRRT, lower intensity CRRT, higher intensity IRRT, and lower intensity IRRT also showed no significance [Supplements 6[Additional file 6] and [Figure 9], [Figure 10], [Figure 11].
Figure 9: The renal recovery rate of the comparison of the higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT

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Figure 10: The length of intensive care unit stay of the comparison of the higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT

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Figure 11: The renal recovery rate of the comparison of the higher intensity continuous renal replacement treatment, lower intensity continuous renal replacement treatment, higher intensity IRRT, and lower intensity IRRT

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  Discussion Top


The present study showed that the outcomes of a meta-analysis comparing high-intensity and low-intensity RRT, including the short-term mortality, renal recovery rate, length of ICU stay, and length of hospitalization, were not statistically significant. Even in the further analysis that compared the high-intensity and low-intensity modes of CRRT and IRRT, the results were not statistically significant.

No studies have shown that AKI patients treated with continuous therapies compared to IHD have greater survival rates,[27],[28],[29] but recent studies tend to suggest that the intensity has no effect on patients.

Ronco et al. conducted a prospective randomized study on the effect of different ultrafiltration doses of CRRT on survival; 425 patients were enrolled, and the study showed that ultrafiltration should be prescribed according to the patient's bodyweight and the rate should be at least 35 mL/kg/h.[9] The study of Saudan et al. showed that when the prescribed effluent flow increased from 25 mL/kg/h to approximately 43 mL/kg/h, all-cause mortality at 90 days decreased from 61% to 41%.[24] However, the above-mentioned studies were only single-center RCTs and thus lacked large-scale multicenter data.

Bellomo et al. conducted a multicentric, randomized trial to compare the effect of the intensity of CRRT and found that treatment with higher intensity CRRT did not reduce the mortality at 90 days.[19] Another randomized study comparing high-volume hemofiltration (HVHF) (65 mL/kg/h) and low-volume hemofiltration (LVHF) (35 mL/kg/h) did not reveal any benefit on survival for HVHF.[25]

Similar results have been shown in the two recent meta-analyses. A study of Van Wert et al. including 12 trials has shown that high-dose RRT is not associated with mortality or dialysis dependency among survivors. Zhang et al.[12] analyzed the effect of intensive-dose CRRT on mortality and other clinical outcomes. Their results also indicated that intensive-dose CRRT had no beneficial effects on clinical outcomes and that more complications occurred in the group treated with intensive-dose CRRT. These results are consistent with our findings.

We categorized the arms within trials as higher intensity and lower intensity based on a consensus among the investigators. The dosages of higher- and lower-intensity CRRT in our trial were similar to the dosages usually prescribed in ICUs in Australia and New Zealand.[30] Another random experiment classified patients according to whether they received either 35 mL/kg/h for the high dosage or 20 mL/kg/h for the standard dosage.[10] In a prospective randomized study, the effective ultrafiltration volume was 32 mL/kg/h in the LVHF group and 62 mL/kg/h in the HVHF group.[25] Consequently, we chose a value of 35 mL/kg/h, which was intermediate between the higher and lower doses in the above studies.

For IRRT, we chose a value of six times a week to distinguish between high and low intensities, as this value was similar to that of the higher intensity treatment group in the study by Palevsky et al.[11] More fundamentally, the concept of the RRT dose as defined by urea clearance does not allow for other considerations, such as the clearance of inflammatory mediators or the achievement of the desired fluid balance. It also presents operational challenges because no commonly accepted method of expressing the dose across RRT patterns exists.[31] Despite these limitations, urea clearance remains a widely used method to measure the RRT dose.[32]

A meta-analysis comparing high- versus standard-dose CRRT (>30 mL/kg/h vs. <30 mL/kg/h), IHD, or SLED (daily vs. alternate day or by target biochemistry) including 12 trials was performed by Van Wert et al.;[32] however, some trials were quasi-randomized, which could not guarantee the quality of the experiments. These trials did not meet our inclusion criteria. The trials included in our experiment were all RCTs.

To further investigate the effect of the pattern of RRT, we performed a network analysis of trials comparing higher intensity CRRT, lower intensity CRRT, higher intensity IRRT, and lower intensity IRRT to investigate the joint effects of the strength and pattern. A specific problem in treating these patients is hemodynamic instability, which frequently requires high doses of catecholamines and large amounts of volume expanders. These patients are also typically hypercatabolic. These comorbidities must be taken into account when choosing extracorporeal RRT.[33] Current treatment strategies for patients with renal failure in the ICU concentrate on the highest possible efficiency of the elimination of uremic toxins in addition to gentile volume removal.[9],[27]

We must emphasize that our study has important limitations. All patients were acute renal injury patients, but some patients also had multiorgan failure or suffered from sepsis or ARF after major surgery. The dialysis membrane materials, anticoagulant drugs, liquid component of the RRT, and timing of dialysis initiation were not standardized, which may have affected the outcomes. We cannot exclude the possibility that some patients may have benefited from personalized prescriptions. In addition, studies have investigated only a single mode, which leads to obvious heterogeneity. Another unanswered question is whether very-high-dose RRT improves outcomes compared to high-dose RRT. A 20-patient RCT found that norepinephrine requirements were reduced in patients receiving CVVH at 65 mL/kg/h compared to those receiving 35 mL/kg/h.[25] Consequently, a meta-analysis comparing very-high-dose versus high-dose strategies in AKI patients should be conducted to provide more information.


  Conclusions Top


Our study has implications for clinical practice in countries where CRRT is now the preferred form of RRT in the ICU. We found that a prescribed treatment intensity that exceeds 35 mL/kg/h for CRRT and exceeds six times a week for IRRT adds no significant benefit. Because we only chose one value as the critical point, our findings do not conclude that the intensity of RRT is unimportant but rather suggests that increases beyond an adequate level of intensity provide no additional benefit for AKI patients.

Supplementary materials

Supplementary data to this article can be found online at the official website of the journal.

Financial support and sponsorship

This study was funded by the National Natural Science Foundation of China (Nos. 81402462, 81571871 and 81770276), Nn10 program, Distinguished Young Scholars Fund of Harbin Medical University Cancer Hospital, the Yuweihan Fund for Distinguished Young Scholars of Harbin Medical University, Harbin Science and Technology Innovation Scholar Fund (2017RAXXJ087), and Heilongjiang Province Postdoctoral Research Fund.

Conflicts of interest

There are no conflicts of interest.



 
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