Long-term Complications After Liver Transplantation K. Kuramitsu, T. Fukumoto, T. Iwasaki, M. Tominaga, I. Matsumoto, T. Ajiki, and Y. Ku ABSTRACT Background. Along with an increased number of cases of liver transplantation (LT), perioperative mortality has decreased and short-term survival has improved. However, long-term complications have not been fully elucidated today. Purpose. Chronic complications were analyzed individually to find risk factors and to improve long-term outcomes after LT. Subjects. There were 63 cases of LT from our outpatient clinic that were included in this study. Among them, 58 were performed using living donor LT and 5 were performed using deceased donor LT. Original diseases mainly consisted of hepatitis C virus (HCV; 45.9%) and hepatitis B virus (23.0%). Findings. The median follow-up was 5.4 3.3 years (range, 0.1w17 years). Overall survival at 2, 3, 5, and 10 years was 89.3%, 83.4%, 81.3%, and 81.3%, respectively. Long-term complications mainly consisted of renal dysfunction (62.7%), dyslipidemia (29.4%), diabetes mellitus (21.6%), and arterial hypertension (21.6%). In univariate analysis, HCV (P ¼ .03) and elapsed years after LT (P ¼ .02) were identified as predictive factors for arterial hypertension and recipient age >50 (P ¼ .03), and elapsed years after LT for renal dysfunction (P ¼ .03), respectively. In multivariate Cox regression analysis, HCV (odds ratio [OR] 5.25, 95% confidence interval [CI] 1.05e34.06, P ¼ .04) was identified as a predictive factor for arterial hypertension, and recipient age older than 50 years for renal dysfunction (OR 5.67, 95% CI 1.34e28.88, P ¼ .02). The number of elapsed years after transplantation was also identified as a predictive factor for arterial hypertension/dyslipidemia/renal dysfunction (OR 13.88/ 14.15/4.10, 95% CI 1.91e298.26/2.18e290.78/1.09e18.03, P ¼ .01/.003/.04). Fifty percent of the recipients developed renal dysfunction within 8 years after LT, and fluctuation of estimated glomerular filtration rate (eGFR) within 3 months after LT was successfully associated with an annual decrease of eGFR (r2 value ¼ 0.574, P < .0001). Conclusion. Renal dysfunction is the most frequent chronic complication after LT. As chronic individual eGFR can be now accurately predicted with deterioration speed, recipient strata for renal protection strategies should be precisely targeted.
S
INCE the first liver transplantation (LT) was performed in 1963 [1], short-term survival has improved rapidly [2]. Along with an improvement in surgical techniques, an immunosuppression regimen that is highly effective for antirejection, and management of infections, long-term survival after LT has significantly improved in recent years. Currently, median survival is reported to be 90% at 1 year and long-term survival to be 60% at 10 years [3]. In Japan, more than 6000 cases of both living (LDLTs) and deceased donor transplantations (DDLTs) were performed ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 797e803 (2014)
until 2012, and patient survival after DDLT was reported to be 80.5% at 1 year and 68.5% at 10 years, whereas that From the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Japan. Address reprint requests to Takumi Fukumoto, MD, PhD, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe City, Hyogo, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.047 797
798
after LDLT was reported to be 83.4% at 1 year and 72.4% at 10 years [4]. As both DDLT and LDLT is now established as a treatment option for end-stage liver disease all over the world, the number of the long-term survivor recipients continues to increase year after year. Longer lengths of follow-up inevitably require subsequent increased exposure to immunosuppression. As patients who require long-term immunosuppression are at higher risk of developing cardiovascular disease [2,5e8], de novo malignancy [7,9], infections, and renal dysfunction [10,11], several studies have already performed analysis focusing on these complications. However, there are few studies which focused on the incidence of overall chronic complications, the risk factors, and predictive factors to decrease patient mortality from these complications. In this study, we first analyzed the incidence of chronic complications after LT. Second, we sought risk factors to develop each of the chronic complications. As renal dysfunction was the most frequent chronic complication among all patients in our study, we finally tracked individual estimated glomerular filtration rate (eGFR) over time and identified a predictive factor to assess chronic renal function with deterioration speed. Within our knowledge, this is the first study to assess individual deterioration speed of renal function and its predictor. We believe the study can target recipient strata where modulatory treatment works most beneficially, resulting in superior outcomes after LT. METHODS All the liver transplant recipients who were included in our study survived more than 1 year and were followed up at our outpatient.
Liver Transplantation For LDLT, donors were selected from parents, grandparents, siblings, offspring, and spouses of their recipients. Preoperative evaluation for estimating graft and remnant liver volume in the donor were performed using three-dimensional reconstructed images of the hepatic vascular anatomy, which was produced using a software package based on the reconstructed images from a multidetector computed tomography (CT) scan of the liver. Resection lines were selected according to this estimated CT volumetry, aiming to obtain 0.6% or more graft weight compared to the recipient body weight. We rejected a donor if the remnant liver volume was less than 30%. All LDLT and DDLT procedures for both donors and the recipients were performed according to methods reported elsewhere [12,13]. The immunosuppressant regimen consisted of tacrolimus and low-dose steroid administration. The dosage of tacrolimus was changed according to the trough level: 10e15 ng/mL for the first month, 5e10 ng/mL for the first year, and approximately 5 ng/mL thereafter. Steroid was withdrawn within 6 months after LDLT as a protocol.
Long-term Complications After discharge, recipients received follow-up examinations at our outpatient clinic based on their conditions between once per week and once every 2 months. Each time, blood chemistries and the trough level of immunosuppressant were measured. Abdominal CT scans were performed every year to detect abdominal malignant tumors.
KURAMITSU, FUKUMOTO, IWASAKI ET AL Magnetic resonance cholangiopancreatography was performed ever year to detect bile duct complications. For recipients with hepatitis C virus (HCV), combined pegylated interferon (PEG-IFN) and ribavirin treatment was introduced 1 to 3 months after LT. A protocol biopsy was performed to confirm the pathological graft fibrosis status and the recurrence of original disease annually for recipients with HCV and primary biliary cirrhosis. Patient survival, causes of mortality, and complications were analyzed in the study. The date of the most recent hospital visit was considered the last follow-up among surviving recipients to a maximum set in June 2013. Long-term complications, arterial hypertension, diabetes mellitus, dyslipidemia, and renal dysfunction were evaluated. Among the characteristics of the recipients, gender, etiology of original disease, recipient age, and the number of years elapsed after transplantation were evaluated as predictive factors for long-term complications.
Definitions The following definitions were used in the study: 1. Arterial hypertension: systolic blood pressure 140 mm Hg and/or diastolic blood pressure of 90 mm Hg, in at least three consecutive evaluations or the need for antihypertensive treatment [14]. 2. Diabetes mellitus: fasting glycemia 126 mg/dL or 200 mg/dL at any time during the day, in at least three consecutive tests, or the need for anti-diabetic agents [15]. 3. Dyslipidemia: fasting cholesterol and/or triglyceride levels higher than 240 mg/dL and 150 mg/dL, respectively, in at least three consecutive blood tests or the need for anti-lipidemic agents [16]. 4. Renal dysfunction: Renal function was accessed by measuring glomerular filtration rate (GFR). GFRs are expressed as mL/ min/1.73 m2, and estimated GFR (eGFR) was calculated using the Schwartz formula [17]. Renal dysfunction was diagnosed either by eGFR of 50 No Yes DDLT No Yes >5 years No Yes
No
Yes
26 14
Diabetes mellitus P
No
Yes
3 8
.03
23 17
34 6
11 0
.17
18 22
2 9
36 4 19 21
Dyslipidemia P
No
Yes
6 5
.86
21 16
34 6
11 0
.17
.11
16 24
4 7
9 2
.46
36 4
1 0
.02
18 22
Renal dysfunction P
No
Yes
P
8 6
.98
12 7
17 15
.48
34 3
11 3
.19
15 4
30 2
.11
.83
13 24
7 7
.33
11 9
8 23
.03
9 2
.46
31 6
14 0
.11
18 27
1 5
.27
2 9
.11
18 19
2 12
.07
11 8
9 23
.03
Abbreviations: HCV, hepatitis C virus; PBC, primary biliary cirrhosis; DDLT, deceased donor liver transplantation.
Individual Progression Pattern of eGFR After LT
DeGFR Correlated With Annual Decrease of eGFR
Because renal dysfunction was the most frequent long-term complication (a notable 50% of the recipients developed renal dysfunction within 8 years after LT), individual fluctuations of eGFR were further analyzed. Figure 3A shows the course of the decreasing levels of eGFR from the time of pretransplantation for all of the recipients. After LT, eGFR levels decreased rapidly within 10 days (56.2w19.7, average 19.9 19.8 mL/min/1.73 m2) and reached the lowest level within 20 days (63.7w12.2, average 31.0 21.7 mL/min/1.73 m2). Although there was a slight recovery during the following 2 to 3 months, these levels were persistently lower compared to the original level (83.6w21.6, average 22.3 18.4 mL/min/1.73 m2 at 3 months), and started to decrease again afterwards (83.5w27.5, an average of 27.6 19.8 mL/min/1.73 m2 at 6 months). As eGFR showed the most drastic change during the first 3 months after LT, DeGFR, which should most precisely and directly reflect individual fluctuation of perioperative eGFR, was subsequently calculated by subtracting the lowest from the highest level of eGFR during the first 3 months after LDLT. Figure 3B shows distribution of DeGFR for each of the recipients. DeGFR varied greatly for each individual recipient, and ranged from 8.9 to 61.3 mL/min/1.73 m2 (average, 31.6 11.5 mL/min/1.73 m2).
To access chronic renal function with deterioration speed, the annual decreases of eGFR levels were calculated. Annual decreases in eGFR levels individually ranged from 6.6 to 1.175 mL/min/1.73 m2 (average, 1.6 1.9 mL/ min/1.73 m2). Searching for a predictive factor, preoperative eGFR, eGFR at month 3, and DeGFR were finally analyzed and associated with annual decreases in eGFR levels. Preoperative eGFR levels ranged individually from 51.1 to 178.1 mL/min/1.73 m2 (average, 87.1 18.5 mL/min/1.73 m2), and revealed no correlation with annual decreases of eGFR levels (Figure 4A) (r2 value ¼ 0.027, P ¼ .422). eGFR at month 3 ranged individually from 33.2 to 128.5 mL/min/1.73 m2 (average, 64.8 17.8 mL/min/1.73 m2), and still revealed no correlation with annual decreases in eGFR levels (Figure 4B) (r2 value ¼ 0.049, P ¼ .278). An association with DeGFR was finally assessed, revealing strong correlation (Figure 4C) (r2 value ¼ 0.574, P < .0001). From the linear fit, DeGFR is now calculated as follows: DeGFR ¼ 23.224.88* annual decrease of eGFR. DISCUSSION
In our study, renal dysfunction was the most frequent complication after LT. The incidence of renal dysfunction increased
Table 4. Multivariate Analysis of Factors Associated With Long-Term Complications Arterial hypertension
HCV PBC Age >50 DDLT >5 years
Diabetes mellitus
Dyslipidemia
Renal dysfunction
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
5.25 1.01 4.23 2.62 13.88
1.05e34.06 0.81e1.68 0.69e41.28 0.22e33.24 1.91e298.26
.04 .40 .12 .43 .01
0.89 0.14 1.14 1.73 3.12
0.20e3.79 0.77e1.28 0.25e5.68 0.20e12.29 0.66e22.77
.87 .14 .87 .59 .16
2.41 10.13 0.39 9.25 14.15
0.49e13.95 0.89e267.48 0.07e1.81 1.25e125.28 2.18e290.78
.29 .06 .23 .07 .003
0.82 0.56 5.67 7.46 4.10
0.18e3.49 0.05e5.22 1.34e28.88 0.73e193.55 1.09e18.03
.79 .61 .02 .09 .04
Abbreviations: HCV, hepatitis C virus; PBC, primary biliary cirrhosis; DDLT, deceased donor liver transplantation.
COMPLICATIONS AFTER LIVER TRANSPLANTATION
A
801
A
B B
C Fig 3. (A) eGFR decrease after LDLT (months). (B) DeGFR during the first 3 months.
Fig 2. Cumulative incidence over time (days) of (A) arterial hypertension, (B) dyslipidemia, and (C) renal dysfunction.
along with the number of elapsed years after transplantation, and recipient age older than 50 years was identified as a risk factor for renal dysfunction. Individual eGFR showed the most drastic change during the first 3 months after LT, and fluctuation of eGFR during this period revealed a strong correlation with an annual decrease of eGFR. Although most programs evaluate the results of LT in terms of patient and graft survival, little has been reported
on the overall chronic complications after LT. To evaluate long-term outcomes of LT, we must consider both transplant-related complications and potential risks to develop other non-transplantrelated aging diseases. Up to now, there are two major studies that have analyzed overall chronic complications after LT, one from the United States in 2000 [22], and the other from Europe in 2013 [23]. In the former work, chronic complications of transplant recipients were compared to the expected incidence based on US population rates revealing significantly higher overall prevalence of hypertension, diabetes, and de novo malignancies. In the latter work from Europe, arterial hypertension, dyslipidemia, renal insufficiency, diabetes mellitus, and obesity are the most common diseases found 10 years post-LT; these may have developed without clinical complications as early as 1 year post-LT. In our study, renal dysfunction, dyslipidemia, diabetes mellitus, and arterial hypertension were the major chronic complications; these findings are similar to the published data. In our study, the rate of these complications over time was also
802
KURAMITSU, FUKUMOTO, IWASAKI ET AL
A
B
C
Fig 4. (A) Pre-eGFR (B) 3meGFR. (C) DGFR.
over
annual
decrease
of
eGFR.
shown to increase, suggesting that our data background is similar despite the small number of cases. Chronic kidney disease after LT is a well-recognized complication, with the initial report in 1998 [24]. Various donor and recipient factors have been reported to associate with chronic kidney disease to date, and a current topic in this field is the search for a precise and valuable predictor and formulating a strategy to prevent the development or progression of chronic kidney disease. From our data, it is now revealed that 50% of the recipients developed renal dysfunction within as early as 8 years after LT. This data is undisputedly discouraging despite the recent encouraging short- and long-term patient survival rates. Although all of the previous analyses might be important to stratify the recipients who will develop chronic kidney disease more accurately [21,25], and accordingly we have no clue to separate patients who still suffer progressively from renal dysfunction at chronic phase. Revealing a novel predictor to assess the deterioration rate of renal function would have a huge clinical relevance and enables us to develop a tailormade renal sparing strategy for each recipient. From our detailed analysis of individual progression patterns, it is now revealed that eGFR fluctuates most drastically within 3 months after LT, and that renal function of recipients who developed a severe eGFR decrease during the same period will deteriorate rapidly at chronic phase. The annual decrease of eGFR can be now calculated as follows: annual decrease of eGFR ¼ (23.22DeGFR)/4.88. Based on this calculation, we propose a novel postoperative strategy. For the recipients who have severe eGFR level decreases within 3 months after LT, the immunosuppressant regimen should be re-established, including the reduction or convention to less nephrotoxic drugs such as the mammalian target of rapamycin inhibitor or mycophenolate mofetil [26e30]. Additionally, previously detected risk factors of preoperative eGFR [19,20] and eGFR at month 3 [21] did not correlate with the annual decrease of eGFR, which successfully showed the shortcomings of the risk factors for chronic kidney disease and emphasized the importance of assessing individual deterioration speed. Unfortunately, we could not elucidate the detailed process of how DeGFR works to predict deterioration speed of individual eGFR. One possible key factor might be the period of postoperative time during which time eGFR revealed a most drastic change. The first 3 months after LT is the most invasive phase and the recipient are exposed to various damages including mechanical, surgical, and druginduced damages. Under the circumstance, eGFR fluctuates most drastically during the entire period after LT. DeGFR, which is defined as the fluctuation of eGFR during the corresponding time, can be positioned as a stress test to detect the damage which will be added afterwards. Renal function of the recipients with higher DeGFR is more fragile to the perioperative stress and accordingly it will
COMPLICATIONS AFTER LIVER TRANSPLANTATION
deteriorate more rapidly at chronic phase compared to the recipients with lower DeGFR. These are still speculations, and further analysis is necessary to prove our results with underlying mechanism. In conclusion, renal dysfunction is the most frequent chronic complication and its incidence increases along with the number of elapsed years after transplantation. Individual decreases of eGFR levels can be now assessed from the fluctuation of eGFR within 3 months after LT. Although our study has the limitations of being a small retrospective study, we believe our novel predictor can reduce the number of the recipients suffering from renal dysfunction, thereby decreasing the morbidity and mortality in the long run after liver transplantation.
REFERENCES [1] Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659e76. [2] Pfitzmann R, Nussler NC, Hippler-Benscheidt M, Neuhaus R, Neuhaus P. Long-term results after liver transplantation. Transpl Int 2008;21:234e46. [3] Carithers RL Jr. Liver transplantation. American Association for the Study of Liver Diseases. Liver Transpl 2000;6:122. [4] The Japanese Liver Transplantation Society. Liver transplantation in Japan d Registry by the Japanese Liver Transplantation Society d Ishoku. 2012;46:524e536. [5] Guckelberger O, Byram A, Klupp J, Neumann UP, Glanemann M, Stockmann M. Coronary event rates in liver transplant recipients reflect the increased prevalence of cardiovascular risk-factors. Transpl Int 2005;18:967e74. [6] Parekh J, Corley DA, Feng S. Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation. Am J Transplant 2012;12:2181e7. [7] Sheiner PA, Magliocca JF, Bordian CA, Kim-Schluger L, Altaca G, Guarrera JV. Long-term medical complication in patients surviving > or ¼ 5 years after liver transplant. Transplantation 2000;69:781e9. [8] Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl 2011;17:15e22. [9] Fung JJ, Jain A, Kwak EJ, Kusne S, Dvorchik I, Eghtesad B. De novo malignancies after liver transplantation: a major cause of late death. Liver Transpl 2001;7:S109e18. [10] Barkmann A, Nashan B, Schmidt HH, Boker KH, Emmanouilidis N, Rosenau J. Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil. Transplantation 2000;63:1886e90. [11] Cohen AJ, Stegall MD, Rosen CB, Wiesner RH, Leung N, Kremers WK. Chronic renal dysfunction late after liver transplantation. Liver Transpl 2002;8:916e21. [12] Broelsch CE, Whitington PF, Emond JC, Wiesner RH, Leung N, Kremers WK. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991;214:428e37. [13] Inomata Y, Uemoto S, Asonuma K, Egawa H. Right lobe graft in living donor liver transplantation. Transplantation 2000;69: 258e64.
803 [14] Whitworth JA, World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21: 1983e92. [15] World Health Organization. World Health Organization: Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. Report of a WHO/IDF Consultation. Part 1. Diabetes Mellitus e Diagnosis. Geneva: World Health Organization, 2006. [16] American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the diagnosis and treatment of dyslipidemia and prevention of atherogenesis 2002 Amended Version. AACE Lipid Guidlines. Endocr Pract 2000;2: 165. [17] Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259e63. [18] Levey AS, Coresh J, Balk E, et al. National kidney foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137e47. [19] Davis CL, Gonwa TA, Wilkinson AH. Pathophysiology of renal disease associated with liver disorder: implications for liver transplantation: part I. Liver Transpl 2002;8:91e109. [20] Davis CL, Gonwa TA, Wilkinson AH. Identification of patient best suited for combined liver-kidney transplantation: part II. Liver Transpl 2002;8:193e211. [21] Sanchez EQ, Melton LB, Chinnakotla S, et al. Predicting renal failure after liver transplantation from measured glomerular filtration rate: review of up to 15 years of follow-up. Transplantation 2010;89:232e5. [22] Sheiner PA, Magliocca JF, Bodian CA, et al. Long-term medical complications in patients surviving > or ¼ 5 years after liver transplant. Transplantation 2000;69(5):781e9. [23] Rubin A, Sanchez-Montes C, Aguilera V, et al. Long-term outcome of long-term liver transplant survivors. Transpl Inter 2013;26:740e50. [24] Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation 1998;66:59e66. [25] Cantavorich M, Tchervenkov J, Paraskevas S, et al. Early changes in kidney function predict long-term chronic kidney disease and mortality in patients after liver transplantation. Trasnplantation 2011;92:1358e63. [26] Schlitt HJ, Barkmann A, Boker KHW, et al. Replacement of calcineurin inhibitors with mycophenolate mofetil in livertransplant patients with renal dysfunction: a randomized controlled study. Lancet 2001;357:587e91. [27] Neuberger JM, Mamelok RD, Neuhaus P, et al. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the ReSpECT study. Am J Transpl 2009;9: 327e36. [28] Boudjema K, Camus C, Saliba F, et al. Reduced-dose tacrolimus with mycophenolate mofetil vs standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transp 2011;11: 965e76. [29] Pageaux GP, Rostaing L, Calmus Y, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 2006;12:1755e60. [30] Karie-Guigues S, Janus N, Saliba F, et al. Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study. Liver Transpl 2009;15:1083e91.
S
INCE the first liver transplantation (LT) was performed in 1963 [1], short-term survival has improved rapidly [2]. Along with an improvement in surgical techniques, an immunosuppression regimen that is highly effective for antirejection, and management of infections, long-term survival after LT has significantly improved in recent years. Currently, median survival is reported to be 90% at 1 year and long-term survival to be 60% at 10 years [3]. In Japan, more than 6000 cases of both living (LDLTs) and deceased donor transplantations (DDLTs) were performed ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 797e803 (2014)
until 2012, and patient survival after DDLT was reported to be 80.5% at 1 year and 68.5% at 10 years, whereas that From the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Japan. Address reprint requests to Takumi Fukumoto, MD, PhD, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe City, Hyogo, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.047 797
798
after LDLT was reported to be 83.4% at 1 year and 72.4% at 10 years [4]. As both DDLT and LDLT is now established as a treatment option for end-stage liver disease all over the world, the number of the long-term survivor recipients continues to increase year after year. Longer lengths of follow-up inevitably require subsequent increased exposure to immunosuppression. As patients who require long-term immunosuppression are at higher risk of developing cardiovascular disease [2,5e8], de novo malignancy [7,9], infections, and renal dysfunction [10,11], several studies have already performed analysis focusing on these complications. However, there are few studies which focused on the incidence of overall chronic complications, the risk factors, and predictive factors to decrease patient mortality from these complications. In this study, we first analyzed the incidence of chronic complications after LT. Second, we sought risk factors to develop each of the chronic complications. As renal dysfunction was the most frequent chronic complication among all patients in our study, we finally tracked individual estimated glomerular filtration rate (eGFR) over time and identified a predictive factor to assess chronic renal function with deterioration speed. Within our knowledge, this is the first study to assess individual deterioration speed of renal function and its predictor. We believe the study can target recipient strata where modulatory treatment works most beneficially, resulting in superior outcomes after LT. METHODS All the liver transplant recipients who were included in our study survived more than 1 year and were followed up at our outpatient.
Liver Transplantation For LDLT, donors were selected from parents, grandparents, siblings, offspring, and spouses of their recipients. Preoperative evaluation for estimating graft and remnant liver volume in the donor were performed using three-dimensional reconstructed images of the hepatic vascular anatomy, which was produced using a software package based on the reconstructed images from a multidetector computed tomography (CT) scan of the liver. Resection lines were selected according to this estimated CT volumetry, aiming to obtain 0.6% or more graft weight compared to the recipient body weight. We rejected a donor if the remnant liver volume was less than 30%. All LDLT and DDLT procedures for both donors and the recipients were performed according to methods reported elsewhere [12,13]. The immunosuppressant regimen consisted of tacrolimus and low-dose steroid administration. The dosage of tacrolimus was changed according to the trough level: 10e15 ng/mL for the first month, 5e10 ng/mL for the first year, and approximately 5 ng/mL thereafter. Steroid was withdrawn within 6 months after LDLT as a protocol.
Long-term Complications After discharge, recipients received follow-up examinations at our outpatient clinic based on their conditions between once per week and once every 2 months. Each time, blood chemistries and the trough level of immunosuppressant were measured. Abdominal CT scans were performed every year to detect abdominal malignant tumors.
KURAMITSU, FUKUMOTO, IWASAKI ET AL Magnetic resonance cholangiopancreatography was performed ever year to detect bile duct complications. For recipients with hepatitis C virus (HCV), combined pegylated interferon (PEG-IFN) and ribavirin treatment was introduced 1 to 3 months after LT. A protocol biopsy was performed to confirm the pathological graft fibrosis status and the recurrence of original disease annually for recipients with HCV and primary biliary cirrhosis. Patient survival, causes of mortality, and complications were analyzed in the study. The date of the most recent hospital visit was considered the last follow-up among surviving recipients to a maximum set in June 2013. Long-term complications, arterial hypertension, diabetes mellitus, dyslipidemia, and renal dysfunction were evaluated. Among the characteristics of the recipients, gender, etiology of original disease, recipient age, and the number of years elapsed after transplantation were evaluated as predictive factors for long-term complications.
Definitions The following definitions were used in the study: 1. Arterial hypertension: systolic blood pressure 140 mm Hg and/or diastolic blood pressure of 90 mm Hg, in at least three consecutive evaluations or the need for antihypertensive treatment [14]. 2. Diabetes mellitus: fasting glycemia 126 mg/dL or 200 mg/dL at any time during the day, in at least three consecutive tests, or the need for anti-diabetic agents [15]. 3. Dyslipidemia: fasting cholesterol and/or triglyceride levels higher than 240 mg/dL and 150 mg/dL, respectively, in at least three consecutive blood tests or the need for anti-lipidemic agents [16]. 4. Renal dysfunction: Renal function was accessed by measuring glomerular filtration rate (GFR). GFRs are expressed as mL/ min/1.73 m2, and estimated GFR (eGFR) was calculated using the Schwartz formula [17]. Renal dysfunction was diagnosed either by eGFR of 50 No Yes DDLT No Yes >5 years No Yes
No
Yes
26 14
Diabetes mellitus P
No
Yes
3 8
.03
23 17
34 6
11 0
.17
18 22
2 9
36 4 19 21
Dyslipidemia P
No
Yes
6 5
.86
21 16
34 6
11 0
.17
.11
16 24
4 7
9 2
.46
36 4
1 0
.02
18 22
Renal dysfunction P
No
Yes
P
8 6
.98
12 7
17 15
.48
34 3
11 3
.19
15 4
30 2
.11
.83
13 24
7 7
.33
11 9
8 23
.03
9 2
.46
31 6
14 0
.11
18 27
1 5
.27
2 9
.11
18 19
2 12
.07
11 8
9 23
.03
Abbreviations: HCV, hepatitis C virus; PBC, primary biliary cirrhosis; DDLT, deceased donor liver transplantation.
Individual Progression Pattern of eGFR After LT
DeGFR Correlated With Annual Decrease of eGFR
Because renal dysfunction was the most frequent long-term complication (a notable 50% of the recipients developed renal dysfunction within 8 years after LT), individual fluctuations of eGFR were further analyzed. Figure 3A shows the course of the decreasing levels of eGFR from the time of pretransplantation for all of the recipients. After LT, eGFR levels decreased rapidly within 10 days (56.2w19.7, average 19.9 19.8 mL/min/1.73 m2) and reached the lowest level within 20 days (63.7w12.2, average 31.0 21.7 mL/min/1.73 m2). Although there was a slight recovery during the following 2 to 3 months, these levels were persistently lower compared to the original level (83.6w21.6, average 22.3 18.4 mL/min/1.73 m2 at 3 months), and started to decrease again afterwards (83.5w27.5, an average of 27.6 19.8 mL/min/1.73 m2 at 6 months). As eGFR showed the most drastic change during the first 3 months after LT, DeGFR, which should most precisely and directly reflect individual fluctuation of perioperative eGFR, was subsequently calculated by subtracting the lowest from the highest level of eGFR during the first 3 months after LDLT. Figure 3B shows distribution of DeGFR for each of the recipients. DeGFR varied greatly for each individual recipient, and ranged from 8.9 to 61.3 mL/min/1.73 m2 (average, 31.6 11.5 mL/min/1.73 m2).
To access chronic renal function with deterioration speed, the annual decreases of eGFR levels were calculated. Annual decreases in eGFR levels individually ranged from 6.6 to 1.175 mL/min/1.73 m2 (average, 1.6 1.9 mL/ min/1.73 m2). Searching for a predictive factor, preoperative eGFR, eGFR at month 3, and DeGFR were finally analyzed and associated with annual decreases in eGFR levels. Preoperative eGFR levels ranged individually from 51.1 to 178.1 mL/min/1.73 m2 (average, 87.1 18.5 mL/min/1.73 m2), and revealed no correlation with annual decreases of eGFR levels (Figure 4A) (r2 value ¼ 0.027, P ¼ .422). eGFR at month 3 ranged individually from 33.2 to 128.5 mL/min/1.73 m2 (average, 64.8 17.8 mL/min/1.73 m2), and still revealed no correlation with annual decreases in eGFR levels (Figure 4B) (r2 value ¼ 0.049, P ¼ .278). An association with DeGFR was finally assessed, revealing strong correlation (Figure 4C) (r2 value ¼ 0.574, P < .0001). From the linear fit, DeGFR is now calculated as follows: DeGFR ¼ 23.224.88* annual decrease of eGFR. DISCUSSION
In our study, renal dysfunction was the most frequent complication after LT. The incidence of renal dysfunction increased
Table 4. Multivariate Analysis of Factors Associated With Long-Term Complications Arterial hypertension
HCV PBC Age >50 DDLT >5 years
Diabetes mellitus
Dyslipidemia
Renal dysfunction
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
5.25 1.01 4.23 2.62 13.88
1.05e34.06 0.81e1.68 0.69e41.28 0.22e33.24 1.91e298.26
.04 .40 .12 .43 .01
0.89 0.14 1.14 1.73 3.12
0.20e3.79 0.77e1.28 0.25e5.68 0.20e12.29 0.66e22.77
.87 .14 .87 .59 .16
2.41 10.13 0.39 9.25 14.15
0.49e13.95 0.89e267.48 0.07e1.81 1.25e125.28 2.18e290.78
.29 .06 .23 .07 .003
0.82 0.56 5.67 7.46 4.10
0.18e3.49 0.05e5.22 1.34e28.88 0.73e193.55 1.09e18.03
.79 .61 .02 .09 .04
Abbreviations: HCV, hepatitis C virus; PBC, primary biliary cirrhosis; DDLT, deceased donor liver transplantation.
COMPLICATIONS AFTER LIVER TRANSPLANTATION
A
801
A
B B
C Fig 3. (A) eGFR decrease after LDLT (months). (B) DeGFR during the first 3 months.
Fig 2. Cumulative incidence over time (days) of (A) arterial hypertension, (B) dyslipidemia, and (C) renal dysfunction.
along with the number of elapsed years after transplantation, and recipient age older than 50 years was identified as a risk factor for renal dysfunction. Individual eGFR showed the most drastic change during the first 3 months after LT, and fluctuation of eGFR during this period revealed a strong correlation with an annual decrease of eGFR. Although most programs evaluate the results of LT in terms of patient and graft survival, little has been reported
on the overall chronic complications after LT. To evaluate long-term outcomes of LT, we must consider both transplant-related complications and potential risks to develop other non-transplantrelated aging diseases. Up to now, there are two major studies that have analyzed overall chronic complications after LT, one from the United States in 2000 [22], and the other from Europe in 2013 [23]. In the former work, chronic complications of transplant recipients were compared to the expected incidence based on US population rates revealing significantly higher overall prevalence of hypertension, diabetes, and de novo malignancies. In the latter work from Europe, arterial hypertension, dyslipidemia, renal insufficiency, diabetes mellitus, and obesity are the most common diseases found 10 years post-LT; these may have developed without clinical complications as early as 1 year post-LT. In our study, renal dysfunction, dyslipidemia, diabetes mellitus, and arterial hypertension were the major chronic complications; these findings are similar to the published data. In our study, the rate of these complications over time was also
802
KURAMITSU, FUKUMOTO, IWASAKI ET AL
A
B
C
Fig 4. (A) Pre-eGFR (B) 3meGFR. (C) DGFR.
over
annual
decrease
of
eGFR.
shown to increase, suggesting that our data background is similar despite the small number of cases. Chronic kidney disease after LT is a well-recognized complication, with the initial report in 1998 [24]. Various donor and recipient factors have been reported to associate with chronic kidney disease to date, and a current topic in this field is the search for a precise and valuable predictor and formulating a strategy to prevent the development or progression of chronic kidney disease. From our data, it is now revealed that 50% of the recipients developed renal dysfunction within as early as 8 years after LT. This data is undisputedly discouraging despite the recent encouraging short- and long-term patient survival rates. Although all of the previous analyses might be important to stratify the recipients who will develop chronic kidney disease more accurately [21,25], and accordingly we have no clue to separate patients who still suffer progressively from renal dysfunction at chronic phase. Revealing a novel predictor to assess the deterioration rate of renal function would have a huge clinical relevance and enables us to develop a tailormade renal sparing strategy for each recipient. From our detailed analysis of individual progression patterns, it is now revealed that eGFR fluctuates most drastically within 3 months after LT, and that renal function of recipients who developed a severe eGFR decrease during the same period will deteriorate rapidly at chronic phase. The annual decrease of eGFR can be now calculated as follows: annual decrease of eGFR ¼ (23.22DeGFR)/4.88. Based on this calculation, we propose a novel postoperative strategy. For the recipients who have severe eGFR level decreases within 3 months after LT, the immunosuppressant regimen should be re-established, including the reduction or convention to less nephrotoxic drugs such as the mammalian target of rapamycin inhibitor or mycophenolate mofetil [26e30]. Additionally, previously detected risk factors of preoperative eGFR [19,20] and eGFR at month 3 [21] did not correlate with the annual decrease of eGFR, which successfully showed the shortcomings of the risk factors for chronic kidney disease and emphasized the importance of assessing individual deterioration speed. Unfortunately, we could not elucidate the detailed process of how DeGFR works to predict deterioration speed of individual eGFR. One possible key factor might be the period of postoperative time during which time eGFR revealed a most drastic change. The first 3 months after LT is the most invasive phase and the recipient are exposed to various damages including mechanical, surgical, and druginduced damages. Under the circumstance, eGFR fluctuates most drastically during the entire period after LT. DeGFR, which is defined as the fluctuation of eGFR during the corresponding time, can be positioned as a stress test to detect the damage which will be added afterwards. Renal function of the recipients with higher DeGFR is more fragile to the perioperative stress and accordingly it will
COMPLICATIONS AFTER LIVER TRANSPLANTATION
deteriorate more rapidly at chronic phase compared to the recipients with lower DeGFR. These are still speculations, and further analysis is necessary to prove our results with underlying mechanism. In conclusion, renal dysfunction is the most frequent chronic complication and its incidence increases along with the number of elapsed years after transplantation. Individual decreases of eGFR levels can be now assessed from the fluctuation of eGFR within 3 months after LT. Although our study has the limitations of being a small retrospective study, we believe our novel predictor can reduce the number of the recipients suffering from renal dysfunction, thereby decreasing the morbidity and mortality in the long run after liver transplantation.
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