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Departments of Surgery, Rutgers–New Jersey Medical School, Newark, NJ
Address reprint requests to Baburao Koneru, M.D., Department of Surgery, Rutgers–New Jersey Medical School, 185 South Orange Avenue, MSB Room G595, Newark, NJ 07101-1709. Telephone: 973-972-7226; E-mail: email@example.com
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observed yield minus expected yield per 100 donors
organ procurement organization
prerecovery liver biopsy
United Network for Organ Sharing
With the continued scarcity of livers, the transplantation of marginal livers from brain-dead donors (BDDs) and livers from cardiac death donors has increased. Concurrently, the proportion of unused livers has increased during the past decade. Data from the Scientific Registry of Transplant Recipients show that 21% of available livers were not used in 2010, whereas 15% were not used in 2004.1 Although no uniform definition of a marginal liver BDD exists, typically older donors (age > 60 years), very obese donors, donors with positive hepatitis serologies or other high-risk behaviors, and donors with intracranial malignancies are considered marginal.[2-4] Usually, when a liver is not considered optimal on the basis of clinical, laboratory, or visual criteria, frozen-section biopsy is performed intraoperatively, and the sample is interpreted at the donor hospital (where expertise in liver pathology is often limited). A final decision is made on the basis of clinical and histological information and the state of the intended recipient. The most common reason for discarding livers either during or after organ recovery is steatosis.
Percutaneous prerecovery liver biopsy (PLB), performed several hours before organ recovery, facilitates a more detailed, expert histological examination and a wider dissemination of biopsy information well ahead of organ recovery. This creates the potential to not only decrease futile liver recovery but more importantly improve liver utilization. However, issues of donor selection, logistics, safety, the accuracy and reliability of histological findings, and the clinical utility of PLB have not been well studied in BDDs. Which donors should be biopsied and what the impact of PLB would be on the duration of donor management are unclear. Although liver biopsy is generally considered safe,[6-8] its complications and their consequences for BDDs, who often have tenuous hemodynamic states, have not been well studied. Although several studies have examined the accuracy of multiple core biopsies,[5, 9, 10] the interobserver variability between pathologists with various levels of expertise in liver pathology may be a concern for the donor population.[11-14] Finally, the clinical impact of PLB on liver recovery and utilization from BDDs has not been well studied.
Therefore, a case-control study of BDDs at a single organ procurement organization (OPO) was conducted to examine (1) the clinical characteristics of BDDs undergoing PLB, (2) whether PLB delays organ recovery, (3) the safety of PLB, (4) the concordance between donor hospital and transplant center pathologists in the interpretation of PLB, and (5) whether PLB decreases futile liver recovery and increases the utilization of livers.
PATIENTS AND METHODS
Study Design and Data Collection
This study was conducted at the New Jersey Sharing Network, which is an OPO covering a donor service area of 8.8 million. A case-control design was used. The cases were BDDs who underwent PLB during the study period of January 1, 2008 to January 31, 2013. No PLBs were identified in a review of records from January 1, 2000 to January 1, 2008. Donor records at the OPO were paper-based until 2004. Electronic archival began in 2004 and was fully implemented in 2008. For the years 2004-2008, both electronic and paper records were reviewed. Two types of controls were used. Because the OPO did not use an established protocol for clinical indications for PLB, each case was matched at first with the BDD immediately before and after the case (sequential controls). On the basis of the clinical differences noted during this comparison, a second set of controls was chosen. Each case was matched to 3 controls with respect to age, race, body mass index, hepatitis C antibody status, alcohol abuse, and diabetes (clinical controls). If more than 3 controls were identified for each case, a computer-generated random sequence (Randomization.com) was used for the final selection. Information regarding demographic, laboratory, hemodynamic, pathology, and recovery/transplantation-related variables were extracted from donor records. Laboratory values and vital signs available at the time of biopsy (cases) or at the assumption of care by the OPO (controls) were used for baseline measurements. When the biopsy indication was not explicit, the most plausible reason based on the clinical information was used. When multiple potential reasons existed for the biopsy, only the most likely indication was chosen. Our primary measure of complication was defined as either one or a combination of the following: a drop in the hemoglobin level > 2 g/dL, a decrease in the mean arterial pressure ≥ 30 mm Hg, and a blood transfusion within 24 hours of biopsy. For controls, a 24-hour period of evaluation after the assumption of care by the OPO was used. Secondary complications such as pneumothorax and injury to intra-abdominal organs were noted but were not included in the composite outcome because their occurrence was expected to be very low. Three mutually exclusive clinical outcomes were evaluated for each donor: (1) liver recovery was ruled out before organ recovery commenced; (2) liver recovery commenced, but the liver was not transplanted (the recovery was aborted before liver removal, or the liver was removed and either discarded or sent to research); and (3) liver transplantation was performed. The expected liver yield was calculated with the United Network for Organ Sharing (UNOS) expected organ yield calculator (beta version 1.0; courtesy of the New Jersey Sharing Network) and is expressed as livers transplanted per donor. This study was approved by the New Jersey Medical School institutional review board. A request for an exemption from the need for informed consent was granted. The reporting of this article follows the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology statement.
For cases, biopsy slides were obtained from donor hospitals and were reviewed by the study pathologist (SP) without knowledge of the donor hospital pathologist (DHP) report. Macrosteatosis and microsteatosis were recorded as the percentage of hepatocytes containing 1 large vacuole displacing the nuclei and as the percentage of hepatocytes containing numerous small, fatty inclusions without displacing the nuclei, respectively. They were categorized as <30% or ≥30%, as described previously. The inflammation grade and the fibrosis stage were assessed according to the modified Scheuer system and were scored from 0 to 416; they were categorized as none (score = 0), low (score = 1-2), or high (score = 3-4) for the determination of the weighted κ value.
Continuous data are presented as means and standard deviations or as medians with 25th and 75th percentiles on the basis of the normality of distributions. Discrete data are presented as counts and percentages. Liver yields are expressed as the observed yield minus expected yield per 100 donors (O-E/100) and as the observed yield per expected yield (O/E). O-E/100 has a units of livers per 100 donors. The significance of differences between groups was tested with either the Student t test or the Mann-Whitney U test for continuous data and with Fisher's exact test or the χ test for discrete data. The agreement between the SP and the DHP was assessed with weighted κ reliability tests. A κ score of 0.01 to 0.20 was considered slight, a score of 0.21 to 0.40 was considered fair, a score of 0.41 to 0.60 was considered moderate, a score of 0.61 to 0.80 was considered substantial, and a score of 0.81 to 1.00 was considered to indicate almost perfect agreement. Missing values were excluded from comparisons. We controlled for confounding in the selection of clinical controls, and no statistical methods were used for adjustment. Analyses were performed with SPSS 20 (IBM, Armonk, NY) and GraphPad QuickCalcs (GraphPad Software, Inc., San Diego, CA) for weighted κ values.
Twenty-four cases were identified. Subsequently, 1 case was excluded because of the misrepresentation of an intraoperative biopsy as a PLB. This resulted in 48 sequential controls and 69 clinical controls. During the study period, there were approximately 700 recovered BDDs: 563 livers were recovered by the OPO, and 484 livers were transplanted. The PLB rate was 3.2 per 100 recovered donors. The yearly biopsy rate ranged from 0 per 100 donors in 2011 to 7.7 per 100 donors in 2013. There were several other consented donors who were deemed not eligible for donation on the basis of routine criteria used by the OPO. They were not included in our analyses.
Donor Clinical Characteristics and Indications for PLB
The baseline clinical and laboratory characteristics of the cases and the controls are compared in Table 1. In comparison with the sequential controls, the cases were significantly older and more obese and had higher prevalences of alcohol abuse and hypertension and a lower UNOS expected liver yield. Four of the 23 cases (17.4%) and 5 of the 48 sequential controls (10.4%) were liver-only donors (P = 0.46). There were no differences in donor sex, ethnicity, cause of death, prevalence of diabetes, prevalence of intravenous drug use, positive hepatitis serologies, or any laboratory values (including liver function tests). The cases had a statistically significant but clinically insignificant lower median baseline heart rate (80 versus 90, P = 0.04). There were no significant differences in the baseline clinical and laboratory characteristics between the cases and the clinical controls (Table 1).
Table 1. Baseline Characteristics of Cases and Controls
Cases (n = 23)
Sequential Controls (n = 48)
Clinical Controls (n = 69)
The data are presented as medians and interquartile ranges (25th and 75th percentiles).
The P value is significant (<0.05) in comparison with cases.
Figure 1 presents the various indications for PLB. A history of alcohol use was the most predominant indication for biopsy (48%), and this was followed by obesity (30%), advanced donor age (13%), and positive hepatitis serologies (9%).
Safety of PLB and Delay in Organ Recovery
The incidences of the primary composite, complication, were similar for the cases 8.7% (2/23), the sequential controls 18.8% (9/48, P = 0.46), and the clinical controls 17.4% (12/69, P = 0.50). There were no secondary complications. According to the donor hospital practices and the availability of expertise, an intensivist, an interventional radiologist, or a transplant surgeon performed PLB. Additional details regarding the use of image guidance, the type of needle used, and the number of needle passes were not available because of the limitation of access to donor inpatient records. The interval from the commencement of donor management to organ recovery was significantly longer for the cases (22.4 ± 8.5 hours) versus both the sequential controls (16.5 ± 8.8 hours, P = 0.01) and the clinical controls (15.9 ± 7.0 hours, P = 0.01). In contrast, the intervals between the abdominal incision and aortic cross-clamping were similar for the cases (104.0 ± 47 minutes), the sequential controls (104.3 ± 39 minutes, P = 0.98), and the clinical controls (100.3 ± 45 minutes, P = 0.74). Fifty-one percent of the clinical controls (35/69) underwent intraoperative biopsy, whereas 22% of the cases (5/23 = 0.21739 = 21.7 = 22%) did (P = 0.03).
Interobserver Agreement of Liver Biopsy Findings
In 6 cases (including the misclassified cased that was excluded from the rest of the evaluation), intraoperative liver biopsy was performed. In 1 case, biopsy was performed because the PLB sample was deemed inadequate. In another case, only intraoperative biopsy was performed, and PLB was not performed; this eliminated the donor from the subsequent analysis. In the other 4 cases, biopsy was performed only for comparison with PLB. All 6 intraoperative slides and 17 of the 23 PLB slides were available for review by the SP. A comparison of intraoperative biopsy and PLB was not performed because of the small number of cases. Table 2 presents a comparison of the DHP and the SP. For macrosteatosis, κ was 0.623. No biopsy showed microsteatosis ≥ 30%, and there was complete agreement between the DHP and the SP regarding this histological finding. To evaluate the rates of agreement between the DHP and the SP in the interpretation of inflammation and fibrosis (each with 3 categories), a weighted κ value was used. The weighted κ value was 0.495 for inflammation and 0.627 for fibrosis. Thus, there was substantial agreement between the DHP and the SP in the interpretation of steatosis and fibrosis, whereas the agreement was moderate for inflammation. The DHP, in general, interpreted inflammation and fibrosis at higher grades and stages, respectively, than the SP.
Table 2. Comparison of DHP and SP Interpretations of Liver Biopsy Samples
NOTE: The κ scores were 0.623 for steatosis, 0.495 for inflammation, and 0.627 for fibrosis.
Association of PLB and Futile Liver Recovery
Figure 2 presents flow diagrams of liver recovery for cases (Fig. 2A) and sequential and clinical controls (Fig. 2B). The controls were subdivided into 2 distinct subsets: those who underwent intraoperative biopsy and those who did not. Further analyses (data not shown) revealed that sequential controls undergoing intraoperative biopsy were more similar to cases with respect to age (52 versus 53 years), prevalence of hypertension (83% versus 78%), prevalence of alcohol abuse (22% versus 57%), prevalence of diabetes (39% versus 26%), and expected median liver yield [0.73 versus 0.76 livers/donor].
Table 3 compares the 3 outcomes for the cases and the clinical controls. The proportions of livers that were transplanted were similar in the 2 groups (60.9% versus 59.4%). However, the proportion of livers for which recovery was ruled out was higher for the cases versus the controls (30.4% versus 8.7%), and conversely, the proportion of liver recoveries without transplantation was lower for the cases versus the controls (8.7% versus 31.9%). These differences were statistically significant (P = 0.009).
Table 3. Donor Liver Recovery Outcomes for Cases and Clinical Controls
Liver Recovery Not Attempted [n (%)]
Liver Recovery Commenced, Liver Not Transplanted [n (%)]
PLB and Liver Utilization vis-à-vis UNOS Liver Yield Calculation
Table 4 presents recovered and transplanted livers for the cases and the clinical controls as well as comparisons with what was expected from the UNOS liver yield calculator. In both groups, the observed yield was lower than the expected yield. Also, the cases and the clinical controls did not differ significantly in the 2 UNOS liver utilization metrics: O-E/100 (−3.3 versus −7.9 Livers Transplanted/100 Donors, P = 0.91) and O/E (0.95 versus 0.88, P = 0.55). However, the control group would have been flagged for review by UNOS for O/E (<0.9) and would almost have been flagged for O-E/100 (<−10). When only those donors from whom liver recovery was attempted were analyzed (because the expected yield would have been 0 without an attempt at liver recovery), the differences between the 2 groups became more pronounced, and the difference in O-E/100 approached significance (22.4 versus −3.7 (Livers Transplanted/100 Donors), P = 0.11).
Table 4. Recovered and Transplanted Livers and Observed Liver Yields Versus Those Expected According to the UNOS Liver Yield Calculator for Cases and Clinical Controls
The principal findings of our study are as follows: (1) PLB may have a role in the evaluation of BDDs, who are at increased risk for liver pathology; (2) PLB is logistically feasible without an excessive delay of organ recovery in some BDDs; (3) PLB is safe; (4) the interpretation of PLB at the donor hospital has a high degree of precision; and (5) PLB appears to decrease futile liver recovery. In the only prior similar study in the literature, Ganz et al. reported the use of PLB with frozen-section evaluation in 21 BDDs during a 3-year period. In that series of donors, in which the liver was the only organ being considered for transplantation, PLB was safe. Liver recovery commenced in 9 cases, but only 5 livers were transplanted. Precision and utility were not addressed in that study.
In contrast to PLB in BDDs, considerable literature exists for PLB in living liver donors.[18-22] Because the sensitivity and specificity of imaging studies are suboptimal for the detection of generalized liver parenchymal abnormalities, PLB is used in the evaluation of living liver donors suspected to have such abnormalities.[23-26] Likewise, PLB can be used in the evaluation of select BDDs. The indications for PLB in our study mirror those reported for living liver donors.[18-22] Furthermore, they are in line with a recent report of US registry data showing that the increased rate of liver discards in more recent years is associated with increasing donor age, obesity, diabetes, and alcohol use. Our finding that intraoperative liver biopsy was performed for 43% of the sequential controls and for 56% of the clinical controls suggests the potential for the use of PLB in more BDDs.
Four unique issues require further consideration in the evaluation of PLB in BDDs. The first issue is related to the logistics of PLB. In contrast to living donors, PLB in BDDs is required urgently. Also, unlike in living donors, in whom PLB is performed only at liver transplant centers, PLB in BDDs would be performed in geographically spread out donor hospitals, where there is limited expertise in liver biopsy. Despite the constraints, an adequate amount of biopsy material was obtained from all except 1 BDD. The logistics of performing PLB are likely to vary from one OPO to another and would have an important impact on its use. Whether the delay of several hours in commencing organ recovery associated with PLB has clinical and logistical implications is unclear. Data in the literature show that longer intervals from brain death to organ recovery are not associated with either a decrease in the number of organs recovered or a deterioration in organ function. It is interesting that PLB was not associated with a decreased duration of recovery surgery in comparison with donors undergoing intraoperative biopsy. This could be due to many reasons, including the recovery time of other organs (predominantly thoracic) and the fact that intraoperative biopsy was performed early and recovery was continued during the wait for the results (so the recovery time was minimally influenced).
The second issue is related to the safety of PLB. The reported complication rates after percutaneous liver biopsy in the literature vary from 0% to 6%.[6-8, 18-22] Although the traditional patient-centered issue of pain is not relevant to BDDs, bleeding and other complications are relevant from the perspective of organs to be recovered and transplanted. In our study, the complication rates were similar for the cases and both sets of controls. Although organ recovery was precluded in 1 case because of hemodynamic collapse, 2 similar instances occurred in sequential controls, and this suggested that PLB did not lead to an increased loss of organs due to hemodynamic collapse of the donor. Thus, PLB in our small sample of cases was safe, but this needs further corroboration from future studies.
The third issue is the precision and accuracy of the histological information. Our findings of substantial agreement between the DHP and the SP with respect to clinically relevant domains of steatosis and fibrosis indicate that the DHP interpretation of PLB is precise. However, a lack of intraoperative biopsies for all cases and a lack of information regarding the number of cores obtained during PLB preclude any further evaluation of the accuracy and reliability of PLB in our study.
The final and most important issue is the utility of PLB. Similarly to the findings of Ganz et al., our data provide preliminary evidence for the idea that PLB decreases futile liver recovery. A greater proportion of cases versus clinical controls were ruled out as liver donors before organ recovery commenced, and fewer liver recoveries were aborted for cases versus controls during recovery. One could certainly argue that some or all of the cases who were ruled out as liver donors before recovery commenced may have been ruled out on clinical grounds alone and without PLB. However, because of the pressure of the shortage of donor livers, prevailing clinical practice would favor ruling out organs on the basis of visualization and/or biopsy. Also, it is possible that PLB led to the erroneous exclusion of cases as liver donors when in fact they might have yielded transplantable livers. This is unlikely because the transplantation rates were nearly identical for the cases and the clinical controls. Even though our study did not address the economic aspects, one would expect that by decreasing liver recoveries aborted at various stages of the recovery surgery, PLB would result in cost savings. In our study, PLB led to a shift in decision making in most of the cases from the operating room to an earlier time point. Whether the availability and provision of PLB information at the time of the initial liver offer for a greater number of marginal liver donors would actually result in the utilization of a greater number of livers from such donors is hypothetical and deserves testing in future studies.
Our study has several strengths and limitations. The strengths are (1) its inclusion of multiorgan donors rather than liver-only donors and, therefore, its greater generalizability; (2) its case-control design, which provides a framework for comparison in the absence of randomization; and (3) its novel use of the UNOS expected liver yield calculator as an outcome evaluator, which might be applicable to other donor intervention studies in the future. A principal limitation of our study is the evaluation of an intervention in a nonrandomized setting with the potential for bias at many levels. Also, PLB information was not substantiated by biopsies performed during liver recovery in all cases. Other limitations include its relatively small size and its use of an evaluation instrument that has not been widely validated, the UNOS expected organ yield calculator.
In conclusion, our study provides preliminary evidence for the idea that percutaneous liver biopsy may be useful in select BDDs, does not excessively delay organ recovery, is safe, and is likely to prevent futile liver recovery. Larger retrospective and prospective randomized trials involving multiple OPOs are warranted to further evaluate the safety and reliability of the histological findings of PLB. Even more important is an evaluation of whether the availability of detailed biopsy information (both reports and images) at the time of initial organ sharing would increase liver utilization from marginal donors.
The authors thank the staff at the New Jersey Sharing Network for their cooperation and assistance with several stages of this study.