Intraoperative factors that remained significantly different between the VVB and non-VVB groups after match (Table 3) were included in a multivariable model to identify risk factor for posttransplant AKI. VVB was confirmed as a sole factor that was negatively associated with post-transplant AKI in patients with compromised pretransplant renal function (odds ratio, 0.1; 95% confidence interval, 0.1–0.4; P = .001, Table 4).
Posttransplant renal replacement therapy in 30 days (38.5% vs 45.7%; P = .344) and 1-year recipient survival (12.3% vs 18.8%, log-rank test P = .149, Figure 4) were not significantly different between the VVB and non-VVB groups in patients with compromised pretransplant renal function.
In this retrospective study of 1037 adult patients, we found that post-LT AKI defined by the AKIN definition was common and the use of intraoperative VVB was associated with a lower incidence of posttransplant AKI in selected patients. Specifically, in patients with compromised pretransplant renal function, the incidence of posttransplant AKI was significantly lower in VVB patients compared with that in non-VVB patients.
Our findings have important clinical implications. Today, an increasing number of patients presenting to LT have compromised pretransplant renal function and are subject to develop posttransplant AKI.15 In addition, these patients are older, have more acuity of liver disease, have higher MELD scores, and have more comorbidities.15,21 The intraoperative course is more difficult for these high-risk patients, with fewer being able to tolerate the dynamic hemodynamics during LT.14 Although piggyback technique has some hemodynamic advantages by partially occluding the IVC, it has many surgical drawbacks and is not always feasible for the high-risk patients.6 As classic LT technique with complete IVC cross-clamp remains as a preferred technique in many centers, our findings suggest that the use of VVB in the high-risk patients may be beneficial.
Previous studies evaluating the potential benefits of VVB have limitations in addition to being outdated and lack of uniform definitions. The additional limitations included small sample size, selection bias not adjusted, no control groups, and reports on patient cohorts that had significantly lower medical acuity. The current study is the first to include more than 1000 patients from a single center. Even after dividing patients into 2 populations, each subset still had more than 400 patients. This allowed us to mitigate the selection bias inherent in comparing all patients with and without VVB. Because utilization of VVB is a clinical decision based on patient characteristics and the projected intraoperative course during LT, patients who received VVB were significantly different from those did not receive VVB. Without properly controlling for these differences, results are difficult to interpret. We used propensity match to minimize the selection bias and achieved a good comparability between the 2 groups. In addition to using propensity match, we also used multivariable logistic regression to control intraoperative cofounding factors that occurred during or after VVB. Many of the intraoperative variables that were included in our logistic model were as risk factors for posttransplant AKI in previous studies. The association between VVB and a lower incidence of AKI was demonstrated in both our analyses.
Pretransplant renal function plays an important role in development of posttransplant AKI. As we showed in this study, VVB was associated with significantly lower posttransplant AKI in the subset of recipients with compromised pretransplant renal function. Although the exact mechanism of this selective renal protection is not completely understood, the following may be postulated. First, it has been shown that patients with compromised pretransplant renal function are more sensitive to renal insults during LT.1 In addition, VVB only partially diverts the blood from the cross-clamped IVC with partially restored RRP. Therefore, the protective effect of VVB for kidney may be partial as well. This selective protection may also contribute to our findings that VVB was only associated with significantly lower incidence of posttransplant AKI, but not renal replacement therapy in 30 days after LT. VVB requires priming the circuit, which has potential effect of hemodilution and lower postoperative serum Cr levels. We are not sure whether this hemodilution plays a significant role on low incidence of postoperative AKI in the VVB group because effect of VVB renal protection remained after blood transfusion was controlled in a multivariable model. Finally, the selective protection is also reflected by the conflicting results in previous studies, where contrary results were often seen in different studies, when different methods, markers, and definitions were used, or the same markers were measured in different perioperative stages.8
The fact that the kidneys with normal pretransplant function (Cr <1.2 mg/dL) were not “protected” by VVB is interesting. First, the overall incidence of AKI was higher in patients with normal pretransplant renal function compared with compromised renal function in our study. Our findings seem contradictory to previous studies showing preoperative renal dysfunction is a risk factor for postoperative renal injury or failure. If renal injury is measured in a “late” or “permanent” term, preoperative renal dysfunction is an obvious risk factor. However, the AKIN definition requires the diagnosis of AKI in only 2 days. In addition, it heavily focuses on relative, not absolute, changes in Cr. Therefore, it is possible that under the AKIN definition, patients with relatively normal pretransplant renal function are at a higher risk of posttransplant AKI compared with those with compromised pretransplant renal function.21 Our hypothesis is supported by recent studies showing that the AKIN definition overestimates the incidence of AKI in patients with low baseline Cr and underestimate the incidence in patients with high baseline Cr.22 The diagnosis using AKIN criteria has additional challenges in patients with chronic kidney disease and end-stage liver disease.23,24 Many factors can affect baseline Cr levels in patients with end-stage liver disease. For example, ascites, fluid overload, and decreased muscle mass are very common in patients with end-stage liver disease and are associated with low Cr levels. Finally, VVB was selectively used in patients with more comorbidities including renal dysfunction. Although we used propensity to match patients with and without VVB, it remained possible that some cofounding factors were unmatched. These postulations can be answered only by prospective studies with randomized designs in the future.
Despite stabilizing hemodynamics and offering potential renal protection, the use of VVB is not without additional risks and costs. Performing VVB requires extra time and may increase the graft cold ischemia time that is associated with poorer graft function.25 Furthermore, complications associated with VVB that have been reported include air emboli, thromboembolism, hypothermia, hematoma, lymphocele, and infection.12,26 Because VVB is associated with risks and the benefit is seen only in selected patients, the use of VVB should not recommended for all patients. A decision of using VVB should be considered after benefits and risks are carefully evaluated.
The limitations of this study merit comments. As a retrospective study, it is subject to the usual inherent biases in such studies. Furthermore, the use of VVB was not standardized. Although we used robust propensity match and logistic regression to minimize the selection bias and the impact of confounding factors, potential bias or confounding by indication still remains. It is likely that the average treatment effect of the treated, not the average treatment effect, was estimated due to the match process. In this study, the urine output was not used. It is common that patients with liver disease are oliguric with avid sodium retention but maintain a relatively normal glomerular filtration rate, or have an increased urine output because of diuretic treatment. Therefore, it is widely accepted that the diagnosis of AKI in patients with liver diseases fully depends on the kinetic changes in serum Cr, as applied in our research.2,17 Finally, the selection of VVB is center specific; therefore, generalization of our findings requires caution.
In conclusion, in this large retrospective study, we demonstrated that intraoperative VVB was associated with the significantly lower incidence of AKI in selected patients after LT. Further studies, preferably in randomized controlled designs, to assess the role of intraoperative VVB in posttransplant AKI, are warranted.
Name: Kai Sun, MD.
Contribution: This author helped provide substantial contribution to the design of the work, acquisition, analysis, and interpretation of data, drafting, revising the work, and final approval of the work to be published.
Name: Fu Hong, MD.
Contribution: This author helped provide substantial contribution to the design of the work, acquisition, analysis, and interpretation of data, and final approval of the work to be published.
Name: Yun Wang, BS.
Contribution: This author helped provide substantial contribution to the design of the work, acquisition, analysis, and interpretation of data, drafting and revising the work, and final approval of the study to be published.
Name: Vatche G. Agopian, MD.
Contribution: This author helped provide substantial contribution to the design of the work, acquisition, and interpretation of data, revising the work, and final approval of the study to be published.
Name: Min Yan, MD.
Contribution: This author helped provide substantial contribution to the design of the study and final approval of the study to be published.
Name: Ronald W. Busuttil, MD, PhD.
Contribution: This author helped provide substantial contribution to the design of the study and final approval of the study to be published.
Name: Randolph H. Steadman, MD.
Contribution: This author helped provide substantial contribution to the design of the study, revising the study, and final approval of the study to be published.
Name: Victor W. Xia, MD.
Contribution: This author helped provide substantial contribution to the design of the study, acquisition, analysis, and interpretation of data, drafting and revising the study, and final approval of the study to be published.
This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.
1. Chen J, Singhapricha T, Hu KQ, et al. Postliver transplant acute renal injury and failure by the RIFLE criteria in patients with normal pretransplant serum creatinine concentrations: a matched study. Transplantation. 2011;91:348–353.
2. Hilmi IA, Damian D, Al-Khafaji A, et al. Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes. Br J Anaesth. 2015;114:919–926.
3. Barri YM, Sanchez EQ, Jennings LW, et al. Acute kidney injury following liver transplantation: definition and outcome. Liver Transpl. 2009;15:475–483.
4. Shaw BW Jr, Martin DJ, Marquez JM, et al. Venous bypass in clinical liver transplantation. Ann Surg. 1984;200:524–534.
5. Veroli P, el Hage C, Ecoffey C. Does adult liver transplantation without venovenous bypass result in renal failure? Anesth Analg. 1992;75:489–494.
6. Mossdorf A, Ulmer F, Junge K, et al. Bypass during liver transplantation: anachronism or revival? Liver transplantation using a combined venovenous/portal venous bypass-experiences with 163 liver transplants in a newly established liver transplantation program. Gastroenterol Res Pract. 2015;2015:967951.
7. Estrin JA, Belani KG, Ascher NL, Lura D, Payne W, Najarian JS. Hemodynamic changes on clamping and unclamping of major vessels during liver transplantation. Transplant Proc. 1989;21:3500–3505.
8. Grande L, Rimola A, Cugat E, et al. Effect of venovenous bypass on perioperative renal function in liver transplantation: results of a randomized, controlled trial. Hepatology. 1996;23:1418–1428.
9. Wall WJ, Grant DR, Duff JH, Kutt JL, Ghent CN. Blood transfusion requirements and renal function in patients undergoing liver transplantation without venous bypass. Transplant Proc. 1987;19:17–20.
10. Johnson MW, Powelson JA, Auchincloss H Jr, Delmonico FL, Cosimi AB. Selective use of veno-venous bypass in orthotopic liver transplantation. Clin Transplant. 1996;10:181–185.
11. Fonouni H, Mehrabi A, Soleimani M, Müller SA, Büchler MW, Schmidt J. The need for venovenous bypass in liver transplantation. HPB (Oxford). 2008;10:196–203.
12. Reddy K, Mallett S, Peachey T. Venovenous bypass in orthotopic liver transplantation: time for a rethink? Liver Transpl. 2005;11:741–749.
13. Gurusamy KS, Koti R, Pamecha V, Davidson BR. Veno-venous bypass versus none for liver transplantation. Cochrane Database Syst Rev. 2011:CD007712.
14. Xia VW, Du B, Braunfeld M, et al. Preoperative characteristics and intraoperative transfusion and vasopressor requirements in patients with low vs high MELD scores. Liver Transpl. 2006;12:614–620.
15. Xia VW, Taniguchi M, Steadman RH. The changing face of patients presenting for liver transplantation. Curr Opin Organ Transplant. 2008;13:280–284.
16. Mehta RL, Kellum JA, Shah SV, et al.; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31.
17. Angeli P, Gines P, Wong F, et al.; International Club of Ascites. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64:531–537.
18. Karapanagiotou A, Dimitriadis C, Papadopoulos S, et al. Comparison of RIFLE and AKIN criteria in the evaluation of the frequency of acute kidney injury in post-liver transplantation patients. Transplant Proc. 2014;46:3222–3227.
19. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–3107.
20. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46:399–424.
21. Filomia R, Maimone S, Caccamo G, et al. Acute kidney injury in cirrhotic patients undergoing contrast-enhanced computed tomography. Medicine (Baltimore). 2016;95:e4836.
22. Pan X, Apinyachon W, Xia W, et al. Perioperative complications in liver transplantation using donation after cardiac death grafts: a propensity-matched study. Liver Transpl. 2014;20:823–830.
23. Libório AB, Macedo E, de Queiroz RE, et al. Kidney disease improving global outcomes or creatinine kinetics criteria in acute kidney injury: a proof of concept study. Nephrol Dial Transplant. 2013;28:2779–2787.
24. Levitsky J, O’Leary JG, Asrani S, et al. Protecting the kidney in liver transplant recipients: practice-based recommendations from the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant. 2016;16:2532–2544.
25. Paulsen AW, Whitten CW, Ramsay MA, Klintmalm GB. Considerations for anesthetic management during veno-venous bypass in adult hepatic transplantation. Anesth Analg. 1989;68:489–496.
26. Khoury GF, Mann ME, Porot MJ, Abdul-Rasool IH, Busuttil RW. Air embolism associated with veno-venous bypass during orthotopic liver transplantation. Anesthesiology. 1987;67:848–851.
Supplemental Digital Content
Copyright © 2017 International Anesthesia Research Society