Introduction

Due to the growing need for organs to be transplanted, methods for expanding organ utilization must be explored. One strategy has been increasing the donor pool via increasing donor registrations, promoting living donor transplants, and using extended criteria donors [1, 2]. The second way to increase the number of organs used is to optimize the donor yield. This means making sure available organs are not wasted, as is the case for approximately 20% of deceased donor kidneys in the USA [3]. One way to accomplish this has been by implementing ex vivo hypothermic machine perfusion before transplantation.

While effective in cost and outcomes for optimal donor organs, there is still some controversy about the overall efficacy and outcomes of the marginal and extended donor criteria kidney transplantation preserved either by the traditional static cold storage (SCS) or the ex vivo hypothermic perfusion machine (HMP). Some studies discussed that the static cold storage method is less suitable for use in marginal and extended donor criteria organ transplants, where hypothermic machine perfusion has some advantages, such as the ability for organ function assessment and possible necessary interventions such as adding medications before transplantation and also reducing some adverse events such as ischemic-reperfusion injury (IRI) [4,5,6,7].

This systematic review aims to summarize and assess the literature regarding outcomes for transplant of extended criteria and marginal kidneys preserved by ex vivo hypothermic machine perfusion and possible comparison with the traditional static cold storage method, with particular emphasis on investigating the effect these interventions had on delayed graft function (DGF) and short- and long-term patient and graft survival to due to the controversy surrounding the use of HMP for marginal kidneys.

Methods and Materials

Search Strategy

A systematic literature review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) (Fig. 1). A wide-ranging screening of the National Library of Medicine Database and the Scopus was performed on March 1, 2022, and the last updated on April 3, 2022, in order to identify literature on hypothermic Machine perfusion prior to transplantation in extended donor criteria and marginal kidneys. The following search queries were performed:

  1. 1-

    “Marginal Kidney AND Machine perfusion AND Transplant.”

  2. 2-

    “Marginal Kidney AND donor AND Hypothermic machine perfusion AND Transplant.”

  3. 3-

    “Extended donor criteria kidney AND Machine perfusion AND Transplant.”

  4. 4-

    “Extended donor criteria Kidney AND donor AND Hypothermic machine perfusion AND Transplant.”

Fig. 1
figure 1

Flowchart of the performed systematic literature research [8]

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Additionally, the ClinicalTrials.gov registry of the US National Library of Medicine was searched on March 1, 2022, for the following terms:

“Kidney AND donor AND Machine perfusion AND Transplant”

No clinical trial was identified (Fig. 2).

Fig. 2
figure 2

DGF comparison between the HMP and SCS groups

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Inclusion and Exclusion Criteria

Articles meeting inclusion criteria for this review were published in prospective, retrospective, clinical trials, and systematic reviews about hypothermic machine perfusion prior to transplantation in marginal and extended donor criteria kidneys. Letters, case reports, case series, and video articles were excluded. Also, follow-up studies that reported no further information on the postoperative outcomes of the respective recipients were excluded.

Data Extraction

A three-stage independent screening method was applied by two of the authors (JC and MM). In case of discordance, the corresponding author, RS, was consulted, and the consensus was made via discussion. During stage one of data extraction, the titles and abstracts of all retrieved records were reviewed, and unsuitable studies were excluded. During stage two, full-text articles of the remaining studies were read carefully and assessed for inclusion criteria, and studies without clinical trials were excluded.

During stage three, articles without relevant outcomes were excluded. Extracted data were reviewed and analyzed by all the authors.

Statical Analysis

DGF, 1-year allograft, and patient survival rates were assessed using Cochran’s Q test, and 95% CIs were calculated for the continuous and dichotomous data and reported as an odds ratio (OR) or risk difference (RD). The overall studies comparison was defined as statistically significant when the P value was < 0.05.

Results

A systematic literature search of the National Library of Medicine database and Scopus identified 3224 records. Based on the title and abstract, 3148 papers were excluded, and 76 articles went for full-text analysis. Of these, 44 were excluded as they did not have a clinical outcome. The remaining 32 articles all assessed the outcome of hypothermic machine perfusion. Finally, 16 articles that assessed kidney function and patient outcomes after using hypothermic machine perfusion as part of organ revitalization were included in this systematic review based on the inclusion criteria and follow-ups. Table 1 shows the overall number of studies, the number of cases in each study, and the study type. A total of 15 of the 16 articles reported DGF post-transplant as a part of their study (Table 2), and 9 studies reported an acute rejection rate. However, the studies’ defined time frame for acute rejection differed (Table 3). Seven studies reported their renal allograft recipients’ median length of stay (Table 4). Seven studies followed the post-transplant kidney function by GFR (Table 5), and ten studies used SCr to follow up the kidney function (Table 6); 13 articles followed up on their patients’ allograft survival and reported it as the graft survival rate (Table 7). Nine articles reported their patient survival rate (Table 8).

Table 1 Overall studies meet the inclusion criteria with publication year and the number of cases
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Delayed Graft Function (DGF)

DGF is defined as failure of the renal transplant to function immediately, with the need for dialysis in the first post-transplantation week. Five of fifteen articles that reported the DGF rate found a significant difference when they compared the DGF rate in their SCS group and HMP group, and the DGF rate was higher in the SCS group compared to the HMP group. The remaining ten studies did not see a meaningful difference when they compared the DGF rate between SCS and HMP groups. Figure 1 shows the overall comparison of the DGF rate. The pooled results showed a significantly higher DGF rate in the SCS group compared to the HMP group (OR = 1.64, 95% CI = 1.35–2, P < 0.0001, Pheterogeneity = 0.30, I2 = 14%). Table 2 shows the DGF rate and comparison in different studies.

Table 2 Studies assessed the DGF rate comparison between HMP and SCS in the extended donor criteria kidneys
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Acute Rejection Rate

Of the nine articles that evaluated the acute rejection post-transplant, one study found a significantly higher acute rejection rate in the HMP group. Watson et al. [10] reported an acute rejection of 22% in the SCS group and 7% in the HMP group (P = 0.06). On the other hand, Gallinat et al. [14] study found a completely opposite acute rejection rate. They reported a 38.5% acute rejection rate in the HMP group and 10% in the SCS group (P = 0.01). Table 3 demonstrates the acute rejection rate in different studies.

Table 3 Studies assessed the acute rejection rate comparison between HMP and SCS in the extended donor criteria kidneys
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Length of Stay (LOS)

Only seven studies reported the length of hospital stay for their SCS and HMP group patients. Two studies found a significant difference between the groups. Wang et al. [15] reported a mean of 19.3 days to stay for the SCS group and 12.4 days to stay for the HMP group (P = 0.001). Savoye et al. [17] reported a mean of 17.1 days to stay for the SCS group and 15.6 days to stay for the HMP group (P < 0.001). Table 4 shows the length of hospital stay in different studies.

Table 4 Studies assessed the length of hospital stay comparison between HMP and SCS in the extended donor criteria kidneys
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eGFR

Seven of sixteen articles reported post-transplant GFR. The follow-up duration was from 7 days to 1 year. Yao et al. [13] study was the only one that reported a meaningful difference after comparing GFR between the SCS and HMP groups after 6 months. The mean GFR with standard deviation was 100.8 ± 29.5 ml/min/1.73 m2 in the HMP group and 85.2 ± 20.37 ml/min/1.73 m2 in the SCS group (P = 0.0128). Meister et al. [21] found a meaningful difference after comparing GFR between the SCS and HMP groups after 7 days, but with the 6-month follow-up, the GFR rate was comparable between the groups. Table 5 shows the follow-up duration and the GFR outcome in different studies.

Table 5 Studies assessed the GFR comparison between HMP and SCS in the extended donor criteria kidneys
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Serum Creatinine (SCr)

Ten papers had reported the follow-up serum creatinine. The follow-up duration was from the discharge to 1 year. Four studies reported a meaningful difference after comparing SCr between the SCS and HMP groups, and SCr was lower in the HMP group compared to the SCS group. Table 6 summarizes each group’s follow-up duration and serum creatinine level.

Table 6 Studies assessed the serum creatinine comparison between HMP and SCS in the extended donor criteria kidneys
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Graft Survival

Thirteen studies of the overall 16 studies followed the allograft survival, and 3 reported a meaningful difference between the SCS and HMP groups. Treckmann et al. [11] reported graft survival after 1 year of following up, and it was 80.2% in the SCS group and 92.3% in the HMP group (P = 0.02). Zhong et al. [16] found a meaningful higher graft survival rate in the HMP group after 1 and 3 years of follow-up. The 1-year graft survival rate was 93% in the SCS group vs. 98% in the HMP group (P = 0.026), and the 3-year graft survival rate was 82% in the SCS group vs. 93% in the HMP group (P = 0.036). On the other hand, although Meister et al. [21] found a meaningful difference between the SCS and HMP groups’ graft survival, the outcome was in favor of the SCS group. After 6 months of follow-up, they reported a 100% graft survival, both deaths censored and uncensored for the SCS group and 93% death censored and 87% non-death censored for the HMP group (P = 0.04). Figure 3 shows the overall comparison of the 1-year graft survival rate. The pooled results showed a significant difference in 1-year graft survival rate between the two groups, and the HMP group had a better 1-year graft survival rate (RD = 1.02, 95% CI = 1.00–1.04, P = 0.04, Pheterogeneity = 0.30, I2 = 15%). Table 7 demonstrates the studies with a graft survival assessment.

Fig. 3
figure 3

1-year graft survival comparison between the HMP and SCS groups

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Table 7 Studies assessed the allograft survival rate comparison between HMP and SCS in the extended donor criteria kidneys
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Patient Survival

The follow-up duration for patient survival rate varied from 3 months to 5 years between the studies. Among the nine articles that reported their patient survival rate, only 1 study had a statistically significant difference. Husen et al. [24] followed their cases for 1 year, and the patient survival rate was 98.5% in the SCS group and 92.9% in the HMP group (P = 0.03). Figure 4 shows the overall comparison of the 1-year patient survival rate. The pooled results showed no significant difference in the 1-year patient survival rate between the two groups (RD = 0.98, 95% CI = 0.95–1.01, P = 0.14, Pheterogeneity = 0.31, I2 = 16%). Patient survival outcomes are summarized in Table 8.

Fig. 4
figure 4

1-year patient survival comparison between the HMP and SCS groups

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Table 8 Studies assessed the patient survival rate comparison between HMP and SCS in the extended donor criteria kidneys
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Discussion

Kidney transplantation remains the gold standard and the only definitive treatment for many people living with end-stage renal disease (ESRD), with the alternative being chronic outpatient dialysis. Those on dialysis are constantly inconvenienced by their hours-long dialysis sessions several times per week and are additionally at a high risk of uremia, poor nutritional status, cardiovascular disease, and infection, which can progress to sepsis and death [25]. While it is generally agreed upon those recipients of extended criteria kidneys have inferior outcomes compared to those of standard criteria kidneys, they do have improved survival compared to dialysis patients who remain on the waitlist, and hence there is demand for them [2]. While effective in cost and outcomes for optimal donor organs, traditional static cold storage (SCS) is less suitable for use in marginal organ transplants, where machine perfusion has several attractive advantages. First, it reduces the chances of ischemic-reperfusion injury (IRI), commonly cited as being responsible for poor transplant outcomes [4]. Second, it allows for additional functional assessment of the organ before implantation rather than relying solely on procurement biopsies, which are often of poor quality, and donor statistics [5]. Machine perfusion also improves transplant logistics by eliminating the time constraint inherent to traditional cold storage. Finally, machine perfusion may provide the opportunity to introduce medications or other interventions ex vivo to recondition the organ before implantation. All these factors make machine perfusion highly desirable in the pursuit of increasing the utilization of high-risk organs without needing to jeopardize outcomes. The more this technology can be implemented, the further we can get toward the ultimate goal of closing the gap between the supply and demand of viable kidneys for transplant.

Three different types of machine perfusion are currently being looked at for use in kidney transplantation, characterized by their operating temperature.

  1. 1.

    Hypothermic machine perfusion (HMP) is currently the most widely used method. This operates between 4 and 10 °C, which, similarly to SCS, slows down cellular metabolism, reducing oxygen requirements and ATP depletion. Circulation of perfusate provides nutrients to the organ while toxic metabolites generated during warm ischemia or SCS can be flushed [6].

  2. 2.

    Normothermic machine perfusion (NMP) operates between 35 and 37 °C. This means reducing or even eliminating cold ischemia time (CIT) and the harm caused by these low temperatures. However, the physiological temperature also means physiological cellular metabolism, so for NMP to be viable, the perfusate must contain an oxygen carrier in addition to other nutrients or pharmacological interventions [7].

  3. 3.

    Sub normothermic machine perfusion (SNMP) operates between 20 and 32 °C. This middle ground temperature is targeted to avoid both the organ damage caused by cold temperatures and the increase in metabolism that necessitates the use of an oxygen carrier in the perfusate [7].

In the present review, we demonstrated the application of hypothermic machine perfusion use in extended donor criteria kidneys before transplantation and the outcomes compared to the static cold storage technique. Although the number of cases and the duration of follow-ups are limited, the current data is promising. We found a significantly lower DGF rate in kidneys preserved by HMP compared to SCS (P < 0.00001). The 1-year allograft survival rate also showed the superiority of HMP compared to SCs for post-discard preservation in the extended donor criteria and marginal kidneys. Although some studies found a better GFR in the kidneys preserved by SCS after the first year. The studies that followed their cases for more than a year saw no difference in terms of GFR. Besides, HMP also improves transplant logistics and allocations by eliminating the time constraint inherent to traditional cold storage and also allows the transplant team to choose the proper operation schedule and time.

Wang et al. [15] conducted a matched clinical trial in 2017 and compared the outcome of patients who received a kidney donated after cardiac death that was preserved either by static cold storage or hypothermic machine perfusion. After 6 months of follow-up, they found a superior outcome for the patients in the hypothermic machine group. Initially, they observed a significantly lower DGF rate in the patients who received a kidney that was preserved by a hypothermic machine (16.7% vs. 37.5%, P = 0.03), similar to what we found in the overall comparison. The length of hospital stay was also significantly lower in this group (12.3 days vs. 19.4 days, P = 0.001). The serum creatinine was normalized in both groups after 6 months, but it was significantly lower in the patients who received a kidney that was preserved by a hypothermic machine (1.18 vs. 1.46 mg/dl, P = 0.05). Summers et al. [22] did a similar study in 2020 with more cases in each group. Although all the outcomes were better in the patients who received a kidney that was preserved by a hypothermic machine, the difference was not significant. Husen et al. [24] conducted the same study, but they added oxygen during hypothermic machine perfusion. They reported that they did not see a significant difference between the two groups. Although, they reported a better patient survival rate in the static cold storage group after 1 year of follow-up (98.5% vs. 92.9%, P = 0.03). Twelve patients from the oxygenated hypothermic machine perfusion died within the first year. They reported that 11 of those patients had a functioning graft at the time of death, and the death was not graft related.

Jochmans et al. [26] clinical trial focused on the effect of adding oxygen during hypothermic machine perfusion. They found that adding oxygen significantly reduces the biopsy-proven acute rejection and 1-year graft survival rate. The kidneys that were preserved with oxygenated hypothermic machine perfusion had 14% BPAR compared to 26% in the non-oxygenated hypothermic machine perfusion group (P = 0.04). Three percent of grafts failed within a year in the HMPO2 group and 11% in the non-oxygenated hypothermic machine perfusion group (P = 0.02). Their study focused on one of the most important advantages of machine perfusion compared to the static cold storage method, which is the possibility of doing interventions. They concluded that adding oxygen to the hypothermic machine perfusion can improve the outcomes of marginal kidneys.

Ravaioil et al. [27] study was the first clinical trial that compared the outcome of extended donor criteria kidneys that were preserved by hypothermic oxygenated perfusion (HOPE) and SCS. They reported a significantly higher 1-year graft survival rate when kidneys were preserved using HOPE compared to the SCS group (P = 0.03). They also reported a higher readmission rate in the SCS group after 6 months (P = 0.04). Although the results from all the studies about the efficacy of hypothermic machine perfusion in extended donor criteria kidneys are promising in terms of outcomes, some limitations still need further assessments and investigations. Randomized clinical trials can eliminate important biases in the studies, which results in more accurate data collection and outcomes. Due to the shortage of overall available kidneys for transplantation, designing a randomized clinical trial with a significant number of cases needs a strict plan and the collaboration of kidney transplant centers for a multi-institutional project. Normothermic machine perfusion (NMP) is a novel method that has recently grabbed more attention as some studies show a better outcome compared to HMP. Conducting a randomized clinical trial that compares the outcome of the marginal kidneys that were preserved either by SCS or NMP can better demonstrate the efficacy of using machine perfusion in extended donor criteria and so-called marginal kidneys. Although, there are some logistic limitations for the normothermic machines. Currently, a few companies make normothermic machines and have different device protocols and settings. Still, some studies are needed to establish the best setting for the NMP, which can improve the overall outcomes for patients and reduce post transplants complications.

In conclusion, we found that extended donor criteria and marginal kidneys preserved by HMP had a lower DGF rate and better 1-year allograft survival rate. Additionally, recent studies show that these outcomes can even improve by adding oxygen to the HMP during the preservation and have a superiority over the traditional SCS preservation method.