Machine perfusion versus cold storage of livers: a meta-analysis

Abstract

Different organ preservation methods are key factors influencing the results of liver transplantation. In this study, the outcomes of experimental models receiving donation after cardiac death (DCD) livers preserved through machine perfusion (MP) or static cold storage (CS) were compared by conducting a meta-analysis. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to compare pooled data from two animal species. Twenty-four studies involving MP preservation were included in the meta-analysis. Compared with CS preservation, MP can reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and hyaluronic acid (HA) and the changes in liver weight. By contrast, MP can enhance bile production and portal vein flow (PVF). Alkaline phosphatase (ALP) levels and histological changes significantly differed between the two preservation methods. In conclusion, MP of DCD livers is superior to CS in experimental animals.

Keywords

machine perfusion / cold storage / DCD / meta-analysis

Introduction

Liver transplantation is an effective solution for most patients with end-stage liver disease. This procedure can also improve patient prognosis, survival time, and survival rate. With the development of surgical techniques, perioperative treatment and immunosuppression, the rate of long-term survival following transplantation is approximately 60% regardless of the origin of liver failure, and the incidence of complications is also remarkably decreased [ 1, 2]. However, the incidence of liver dysfunction and other liver diseases ranges from 15% to 20% and leads to a long recovery period, great financial cost, long-term repercussions for liver functions, retransplantation and a high mortality rate [ 2, 3]. Rapidly increasing demands for organ transplantation have also caused a serious lack of donors. Therefore, an innovative method should be developed to address the shortage of donors.

During organ transplantation, a donor liver suffers from ischemia and liver injury. Various methods can modulate ischemia–reperfusion (IR) injury. For instance, appropriate preservation is an effective method to reduce injury. Therefore, the ability of grafts to recover to normal function after reperfusion depends on preservation methods and conditions [ 1]. With advancements in preservation methods and perfusates, the rate of success of organ transplantation increases and thus saves lives for transplantation worldwide [ 4].

Cold storage (CS) has been considered the standard method of organ preservation since the 1960s. The physiological rationale of CS is to maintain ATP depletion at a minimum to inhibit ischemic injury cascades [ 4]. Metabolism slows down by 1.5-fold to 2.0-fold as temperature decreases by 10 °C; however, metabolism continues even at 0 °C [ 4, 5]. Therefore, ATP concentration decreases substantially and IR injury occurs when CS preservation is used to conserve donor organs stored at freezing temperatures (0 °C) in a UW solution. However, the effectiveness of CS preservation and conventional preservation solutions is currently insufficient to satisfy the increasing demands of organ transplantation. Machine perfusion (MP) has reemerged as a preservation method to expand donor pools and to address the severe shortage of organs available for transplantation [ 6]. Consequently, some high-risk donors can be utilized through MP preservation. MP is also recognized as a well-known and potentially superior preservation method.

MP is widely used for organ preservation in kidney transplantation. MP is a preferred method to manage the physiological status and perfusion parameters of donor organs because it can provide continuous circulation of a preservation solution as a “washout effect,” which imitates physiological processes in vivo. Renal MP also reduces the risk of delayed graft function and enhances graft survival [ 7]. This method also improves early graft function and long-term graft survival [ 7, 8]. Oxygenated solutions used for MP can prevent ATP loss and avoid IR injury caused by ATP depletion [ 9– 12] during organ preservation. As a result, MP preservation can reduce IR injury during transplantation and graft failure. However, MP is not currently used in clinical liver transplantations because the hepatic and portal system of the liver must be perfused, hepatic sinusoidal endothelial cells can be easily damaged, and the liver undergoes high metabolism rates [ 13]. Thus, optimal protocols have yet to be established to guide transplantation with MP preservation [ 13]. Moreover, whether MP is more effective than CS remains unknown. Considering these findings and controversies, we conducted a meta-analysis of studies on experimental animals to determine whether MP can yield liver transplantation outcomes superior to those of CS. Although this meta-analysis is limited by its assessment of experimental animals rather than human subjects, this work can help clinical doctors select the optimum preservation method for donor livers to achieve preferable outcomes during transplantation.

Methods

Literature search

The literature search was carried out on PubMed, EMBASE, and Medline by using the terms (MP OR machine perfusion OR machine preservation) AND (CS OR cold storage OR cold preservation) to find abstracts and full papers in which liver was preserved using either MP or CS to determine which preservation method was superior. The search was performed until July 2015. Publications were limited to English articles, and no species constraint was applied in the search. All “Reviews,” “Editorials,” “Books,” “Case reports,” and “Letters” were excluded after limit filtering. References of the relevant literature were also searched. The PRISMA flow diagram was used in the search process.

Inclusion and exclusion criteria

Only studies reporting outcomes of DCD liver transplantation using MP preservation were eligible for this analysis, and the species were limited to pigs, rats, and humans. No perfusion solution or perfusion temperature constraints were applied. The exclusion criteria included the following: (1) studies without a control group (CS preservation group); (2) studies without data; (3) studies conducted using retrospective, non-randomized, and uncontrolled design; and (4) studies published more than 15 years prior to this analysis. Historical transplant operation and preservation techniques may have been significantly different from those performed using current technologies.

Quality evaluation and data extraction

To determine the quality of the selected studies, the ARRIVE guidelines (Table 1) and STAIR guidelines (Table 2) were used for evaluation [ 14, 15]. Two independent reviewers assessed the publications in the final meta-analysis, and the data were extracted from the publications via discussion and consensus on all formulary criteria. The following data were extracted from the selected studies: names of authors; dates of publication; species of the experimental animals; number of CS preservation animals; number of MP preservation animals; preservation time; preservation solution; and changes in AST, ALT, LDH, ALP, bile production, HA, PVF, liver weight, and histology.

Data analysis

Given that the outcomes of several trials used different scales, we calculated the standardized mean difference (SMD) and 95% confidence interval (CI) by using Cohen’s method to convert the outcomes into a common measure [ 40]. We pooled the total effect size by using the random-effects model and assessed the heterogeneity between studies with a Q value and I² statistic value (25%, 50%, and 75% corresponding to the cutoff points for low, moderate, and high degrees of heterogeneity). Statistically significant heterogeneity was established at P<0.1 in Q or I²>50%; otherwise, we declared no obvious heterogeneity. We performed subgroup analyses for each variable according to animal species. Publication bias was examined in funnel plots by performing Begg’s and Egger’s tests. We used STATA software version 12.0 to analyze the data. A two-tailed P<0.05 was accepted as statistically significant.

Results

Eligible studies

One search based on the abovementioned strategies initially identified 102 articles in PubMed, 73 articles in EMBASE, and 70 articles in Medline. After removing duplicates from the searched articles, a total of 111 articles were left for further screening. After screening the electronic abstracts, 82 studies were ruled out because of the exclusion criteria with regard to review articles and studies on other experimental animals. A total of 29 remaining studies were considered to be potentially relevant and were read in full. Among these studies, one study used peritoneal cooling instead of CS as the control group; another study only included a group that used CS preservation initially, followed by MP preservation for hours [ 41, 42]. The 27 remaining studies on MP for liver transplantation received an extensive review. Two of these studies lacked a control group (CS group) [ 43, 44]. One of these studies lacked a comparison between the CS and MP groups [ 45]. As a result, 24 studies involving MP preservation in two species (rats and pigs) were included in the meta-analysis, as shown in the PRISMA flow diagram (Fig. 1) [ 46]. Among these selected publications, 11 and 13 studies used the pig and rat experimental models, respectively.

The median quality scores were determined in accordance with the ARRIVE and STAIR guidelines as 10 (range: 7 to 14) and 3 (range: 1 to 5), correspondingly (Tables 1 and 2).

Hepatocellular injury and function

Twenty-four studies involving a total of 230 animals were reported (Table 3). Most of these studies measured the release of liver enzymes after reperfusion. Nine of the studies that reported ALT levels demonstrated that MP reduced the release of ALT, and the SMD of ALT was -2.22 units (95% CI, -3.01 to -1.43); a significant difference was found between the CS and MP groups (Fig. 2A) [ 17– 19, 21, 25, 28, 30, 32, 38].

Similarly, 10 studies reported that MP reduced the level of AST compared with CS preservation [ 16, 21, 23– 26, 30, 31, 33, 34]. After combining the results of the studies that measured AST, we calculated the SMD of AST to obtain a value of -1.56 units (95% CI, -2.02 to -1.11), and a significant difference was found between the CS and MP groups (Fig. 2B).

We further measured the level of LDH. Half of the selected studies reported LDH [ 16, 21, 23, 25, 26, 28, 29, 31, 33, 34]. Accordingly, a significant difference existed between the two groups, and the SMD of LDH was -1.71 units (95% CI, -2.58 to -0.84) (Fig. 2C).

Biliary epithelial and sinusoidal endothelial injury and function

Two studies reported the ALP level and only used pig models [ 17, 25]. The SMD of ALP was -0.17 units (95% CI, -0.96 to 0.61) (Fig. 3A) (no statistically significant difference).

However, nine studies reported bile production during perfusion, and six of these studies indicated that MP preservation led to increased bile production [ 17– 19, 25, 26, 29– 31, 39]. Moreover, the reports showed a significant difference between the two groups in terms of outcomes. Overall, MP increased bile production by a standardized mean (95% CI) difference of 1.10 (0.01 to 2.18) units (Fig. 3B).

Finally, hyaluronic acid (HA) was used to evaluate the damage to sinusoidal endothelial cells. However, only two studies measured HA, and these studies were conducted using pig models [ 16, 23]. The livers of pig models receiving MP preservation experienced a lower HA level (i.e., less cellular injury) than that of the CS group. The SMD of HA was -1.92 units (95% CI, -3.01 to -0.82). As such, a significant difference was observed between the two groups (Fig. 3C).

Hemodynamics

Six studies reported portal vein flow (PVF), and only two of these studies identified a similar PVF among the two methods of preservation by using pig and rat models [ 18, 25, 26, 30, 31, 39]. The PVF was higher in the MP group than in the CS group by a standardized mean (95% CI) difference of 1.38 (0.38 to 2.38) units, which was statistically significant (Fig. 4).

General and histologic changes

Finally, we further evaluated the graft changes under macroscopic and microscopic observations to assess the effectiveness of MP versus CS. Among all the studies, only three used a pig model to report liver weight changes, and two studies reported significantly different results [ 21, 25, 26]. The SMD was -1.74 units (95% CI, -3.23 to -0.24), and significant differences were observed between the two groups in terms of outcomes (Fig. 5A).

Furthermore, we thoroughly examined the histologic changes in the liver. Although most of the selected studies reported HE liver staining, only two studies used the quantified indexes to evaluate histologic changes [ 30, 31]. As a result, a bias might have existed in our meta-analysis. However, no significant difference was found between the two preservation methods with regard to histologic changes (Fig. 5B).

Test of publication bias

We created a funnel plot to assess the publication bias regarding the effect of MP preservation on the DCD livers of experimental models across all the selected studies. No evidence of publication bias was found in the selected indicators used to evaluate MP preservation (Fig. 6A‒6I).

Discussion

Liver transplantation is an effective solution for most patients with end-stage liver disease. During transplantation, the method of organ preservation is an important factor affecting the prognosis of patients.

To date, CS preservation has become the generally accepted method to preserve organs. However, the potential of CS preservation has approached its limit because of the increasing use of high-risk donors and the growing waiting lists for organ transplantations. To address the large discrepancy between donor supply and demand, new methods are being developed to utilize high-risk donors. As a result, MP preservation has reemerged as a method to expand donor pools.

At present, MP preservation technologies have been applied in clinical kidney transplantation to achieve favorable prognoses [ 47]. MP preservation has been shown to increase graft quality and decrease the incidence of delayed graft function by shortening the period of warm ischemia. MP preservation can also decrease vasospasms and complications after transplantation [ 1]. Moreover, MP enables more control of MP parameters such as cellular pH. Although MP preservation presents various advantages compared with CS, it comes with increased costs, increased complexity, potential endothelial injury, and potential equipment failure [ 1]. In 2003, a meta-analysis on MP concluded that MP was superior over CS in terms of DGF incidence in kidney transplantation [ 48]. Another meta-analysis conducted in 2012 based on prospective RCTs of DCD kidneys showed that MP was superior over CS in reducing the incidence of DGF; however, no difference existed in primary non-function, one-year graft survival, or one-year patient survival [ 3]. Although kidney MP preservation has been used successfully, the application of MP remains challenging in liver transplantation. The optimal tract of perfusion and other optimal parameters for MP preservation in DCD livers remain unknown. Nevertheless, some studies have demonstrated that MP preservation can reduce liver damage in both SCD and DCD by preventing ATP loss and avoiding injurious ischemic cascades [ 4]. Guarrera et al. [ 49– 52]studied the MP preservation used in human liver transplantations and found that MP shortened the expression of proinflammatory cytokines and ICAM-1, as well as decreased the incidence of biliary complications and hepatocellular enzymes. Various other studies that used rat or pig models also found that MP was superior over CS in decreasing hepatocellular enzymes and liver injury [ 16– 19, 24– 26, 28– 32, 38]. In our meta-analysis, AST, ALT, and LDH, which were used to estimate liver viability, showed significant differences after MP compared with those after CS preservation.

Unlike hepatocytes that receive a dual blood supply, the bile duct involves only a single blood supply from the hepatic artery and is more sensitive to ischemic injury [ 53]. Previous studies have shown a 5% to 15% incidence rate of ischemic biliary injury after orthotopic liver transplantation, and this injury may cause early graft dysfunction, graft failure, and retransplantation [ 54]. MP preservation can imitate the physiological status and cause less damage to the biliary epithelia compared with CS preservation. MP preservation can enhance preservation via a continuous supply of oxygen to the endothelium and can assist in avoiding injury to the arterial vasculature of the biliary tree. One study conducted by Dries et al. [ 26] in 2013 indicated that bile production and ALP showed no significant differences between the two groups. However, many studies obtained a contradictory result [ 17, 18, 25, 29– 31]. We found a difference in the bile production but no difference in the ALP level between the two preservation methods. This finding may be attributed to the small amount of ALP data.

HA is a marker for the function of sinusoidal endothelial cells and is selectively and rapidly cleared from the circulation [ 23]. In our meta-analysis, MP preservation is superior over CS in terms of reducing the HA level. However, only experiments that used pig models have measured HA [ 16, 23]. Therefore, the conclusion may be one-sided, and these limitations warrant future studies.

We found no difference in histologic changes between the two preservation methods. This finding may be ascribed to the lack of a unified evaluation criterion. Among the selected studies, only two articles used a quantization criterion for evaluation. Therefore, additional quantization histology data are needed for future research.

MP preservation provides various advantages over CS preservation. However, MP requires additional logistic planning before this method is extensively used in clinical settings. Some limitations exist in our meta-analysis. First, experimental heterogeneity may be retained, although we formulated strictly enrollment criteria. Species may be an important source of heterogeneity in our meta-analysis. Although we stratified the parameters according to species, we found that heterogeneity should be considered for some of the parameters, such as LDH, bile production, and PVF, in the two species. We did not perform a subgroup analysis or meta-regression analysis to explore the source of heterogeneity because few studies were involved in each parameter. The selected studies involved experimental models to compare MP and CS preservation. Recent studies only explored the short-term results of the models. MP may also induce long-term transplantation effects. The selected studies also employed different preservation solutions, perfusion times, and other parameters. Such differences may result in analytical bias. None of the included studies conducted a cost-effective analysis. Therefore, further research should be performed to explore these limitations.

In conclusion, MP preservation of the liver obtained from DCD donors can reduce edema and damages of hepatocellular, biliary epithelial, and sinusoidal endothelial cell. These conditions contribute to a reduced change in liver weight after transplantation compared with those in CS preservation. However, the two preservation methods did not differ in terms of ALP level or histological changes. MP preservation is recommended to expand the donor pool by allowing safe and effective high-risk donor transplantation. This preservation method likely reduces the discrepancy between donor supply and demand and thus improves liver transplantation outcomes.

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