All adult (age ≥ 18 years old) patients undergoing LDLT from January 2007 to May 2009 at the First Affiliated Hospital, Zhejiang University School of Medicine, China were included in this retrospective study. Patients who died within 3 mo of LDLT were excluded. A total of 115 (96 male and 19 female) patients with a mean age of 44.7 ± 10.11 years (median: 46 years, range: 18-64 years) at transplantation were finally included. The indications for LT included cirrhosis (n = 63, 54.8%), acute liver failure (n = 28, 24.3%) and hepatocellular carcinoma (n = 24, 20.9%). Patient characteristics are shown in Table 1. Written informed consent was acquired from all donors and recipients before transplantation. Each organ donation and transplantation at our center was strictly carried out under the guidelines of the Ethics Committee of the First Affiliated Hospital, Zhejiang University, the regulation of Organ Transplant Committee of Zhejiang Province and the Helsinki Declaration of 1975. No prisoners were included in this study.

All patients received a triple immunosuppressive regimen incorporating tacrolimus, prednisolone, and mycophenolate mofetil as described previously[15]. An interleukin (IL)-2 receptor blocker was used in some patients. Prednisolone was withdrawn within the first post-transplant month. A reduced dose of tacrolimus was given to patients who developed post-transplant renal impairment. All patients were routinely followed up at the out-patient clinic and the mean follow-up time was 2.66 ± 1.02 years (median: 1.98 years, range: 0.50-4.63 years).

The data were extracted from the China Liver Transplant Registry (CLTR) database: age (donor/recipient), gender (donor/recipient), underlying liver diseases, cold ischemic time, graft-to-recipient weigh ratio (GR/WR), graft volume to standard liver volume ratio (GV/SLV), donor’s hepatic steatosis, recipient’s pre-transplant metabolic status [history of smoking, alcohol abuse, diabetes mellitus, hypertension, hyperlipidemia, body mass index (BMI)], recipient’s post-transplant liver function (bilirubin, alanine transaminase, aspartate transaminase, cholinesterase and international normalized ratio), recipient’s pre/post-transplant renal function (serum creatinine), donor’s and recipient’s pre/post-transplant serum lipid profile (total triglycerides, total cholesterol), immunosuppressive regimen (agents and plasma levels), and recipient’s post-transplant complications.

Hyperlipidemia was defined as serum triglycerides ≥ 150 mg/dL or serum cholesterol ≥ 200 mg/dL or the need for pharmacologic treatment[16]. Patients were divided into the PTHL group (n = 28) and non-PTHL group (n = 87) according to their serum lipid levels at the sixth month after LDLT. EAD was defined by the presence of at least one of the following features: total bilirubin > 10 mg/dL, prothrombin time ≥ 17 s, or hepatic encephalopathy from day 2 to 7 post-transplantation[17]. ERD was defined as serum creatinine ≥ 2 mg/dL and/or the need for renal replacement therapy in the first post-transplant week[18]. Renal insufficiency was defined as pre-transplant serum creatinine > 1.5 mg/dL[18].

Quantitative variables were presented as mean ± SD or median with range. Categorical variables were expressed as numbers and percentages. The Student’s t test or Mann-Whitney U test was used to compare quantitative variables and the χ² test was used to compare categorical variables. Pearson’s correlation and scatter plot graph were used for correlation analysis. Logistic regression was used to identify the risk factors for PTHL. Variables that were statistically significant in univariate analysis were entered into multivariate analysis. The Kaplan-Meier method and log-rank test were used for survival analysis. SAS software version 9.2 (SAS institute, Cary, NC, United States) was used to complete all the analyses, and a P value of less than 0.05 was considered statistically significant. Data analysis was performed by the CLTR Statistical Department.

Of 115 eligible recipients, 19 (16.5%) had pre-transplant hyperlipidemia and 28 (24.3%) developed PTHL. Of the recipients with and without pre-transplant hyperlipidemia, the incidence of PTHL did not differ significantly (21.1% vs 25%, P = 0.714).

Of 115 donors, 13 (11.3%) were diagnosed with hyperlipidemia and 9 (7.8%) had hepatic steatosis. However, neither donor hyperlipidemia nor hepatic steatosis was found to be differently distributed between the PTHL group and non-PTHL group (both P > 0.05) (Table 1).

Nine recipients (7.8%) developed cardiovascular events, including four with nonfatal myocardial infarction, two with cardiac arrhythmia, one with cardiac arrest and two with stroke, with a mean onset time of 10.5 mo (median: 8 mo, range: 3-15 mo). Compared to the non-PTHL group, the PTHL group had a higher incidence of cardiovascular events after LDLT (n = 5, 17.9% vs n = 4, 4.6%, P = 0.037). The 1- and 3-year cumulative survival rates were 89.3% and 85.7% in the PTHL group, and 97.7% and 85.0% in the non-PTHL group, respectively. There was no statistically significant difference between the two groups in cumulative survival (P = 0.956).

As shown in Figure 1, alanine transaminase, aspartate transaminase and bilirubin, which indicate hepatic cellular injury, decreased sharply in the first post-transplant month and continued to decline to the normal range during the next two months. Cholinesterase, which represents hepatocellular synthetic function, remained at a low level during the first post-transplant month and gradually increased to an ideal level at post-transplant month 3. Of these parameters, cholinesterase had a significant positive correlation with serum cholesterol level at post-transplant month 1 (r = 0.341, P = 0.001) and month 3 (r = 0.280, P = 0.003), respectively (Figure 2A and B). However, cholinesterase was not associated with the development of PTHL following logistic regression analysis (P > 0.05).

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Figure 1 Variation tendency of graft and renal function by post-transplant month 6 in all recipients. A: Alanine/aspartate transaminase; B: Total bilirubin; C: Cholinesterase; D: Serum creatinine. Data were presented as means ± SD.

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Figure 2 Correlation between serum cholesterol and triglyceride level and cholinesterase at post-transplant. A: Correlation between serum cholesterol level and cholinesterase at post-transplant month 1; B: Correlation between serum cholesterol level and cholinesterase at post-transplant month 3; C: Correlation between serum triglyceride level and serum creatinine at post-transplant month 1; D: Correlation between serum triglyceride level and serum creatinine at post-transplant month 3.

EAD occurred in 18 (15.7%) of 115 recipients. At the third post-transplant month, EAD had resolved in 77.8% (14/18) of patients. Primary graft non-function was not observed. The incidence of PTHL did not differ significantly between patients with EAD and those without EAD (33.3% vs 20.6%, P = 0.236).

Serum creatinine levels decreased during the first post-transplant month (Figure 1) and were significantly related to serum triglyceride level at the first (r = 0.440, P < 0.001) and third (r = 0.250, P = 0.007) post-transplant month, respectively (Figure 2C and D). Serum creatinine levels at the first post-transplant month differed significantly between the PTHL and non-PTHL groups (1.10 ± 0.67 mg/dL vs 0.73 ± 0.25 mg/dL, P = 0.001).

ERD occurred in 16 (13.9%) of 115 post-transplant recipients. There was a statistically significant difference between ERD and non-ERD recipients in pre-transplant renal function (Table 2). Serum creatinine remained high during the first 6 post-transplant months in ERD recipients. Of the 16 recipients with ERD, 9 and 5 needed hemodialysis in the first and third post-transplant month, respectively. The prevalence of PTHL in ERD patients was significantly higher than that in non-ERD patients (56.3% vs 19.2%, P = 0.003), notably for hypertriglyceridemia (56.3% vs 12.1%, P < 0.001).

We postulated that donors’ pre-transplant hyperlipidemia and hepatic steatosis, GR/WR (%) and GV/SLV (%); recipients’ pre-transplant serum creatinine level, pre-transplant BMI and pre-transplant hyperlipidemia, post-transplant tacrolimus level, post-transplant diabetes within the first six months after LDLT[15], post-transplant BMI at the sixth month after LDLT, EAD and ERD were potential risk factors for PTHL. Following univariate analysis, five variables were identified as significant risk factors for PTHL and were entered into the multivariate analysis (Table 3). We subsequently found that ERD [odds ratio (OR) = 9.593, P < 0.001] and BMI (OR = 6.358, P = 0.002) were independent risk factors for PTHL.

Post-transplant hyperlipidemia (PTHL) is a major and serious complication after liver transplantation. It is estimated that 45%-70% of recipients develop PTHL, which is well recognized as one of the major risk factors for cardiovascular diseases, including myocardial infarction, ischemic stroke and peripheral arterial disease, and exerts negative effects on the recipient’s long-term survival and quality of life. It is well known that the liver plays an essential role in lipoprotein metabolism and is involved in almost every key step during lipid anabolism and catabolism. More importantly, renal insufficiency, which is common in liver transplant candidates, is closely associated with significant alterations in lipid metabolism. Therefore, it is necessary to determine the associations between both renal and hepatic function and PTHL.

The pathogenesis of PTHL remains to be elucidated. Possible factors which may increase the risk of PTHL include overweight or obesity, advanced age, and the use of immunosuppressive agents. Immunosuppressive drugs were considered to have a major effect on the development of metabolic syndromes in previous years. Today, immunosuppressive drugs are known to have a reduced impact on glucose or lipid metabolism. Low toxicity immunosuppressive protocols (e.g., early withdrawal of steroids and low-dose calcineurin inhibitors) have decreased the impact of immunosuppressive drugs on PTHL.

Over the past few years, most researchers have focused their attention on immunosuppressive protocols and obesity status. However, together with the application of lower toxicity immunosuppressive protocols, an increasing number of articles have shown that novel immunosuppressive therapy has less of an impact on glucose and lipid metabolism. Therefore, authors looked into the possibility that kidney and graft function may have a potential relationship with PTHL. From the results, renal and graft function were shown to correlate with lipid metabolism after living donor liver transplantation. Severe pre-transplant renal insufficiency may lead to long-term post-transplant renal dysfunction, and consequently result in PTHL, especially hypertriglyceridemia. Appropriate clinical treatment such as the prophylactic use of fibrates or statins may prevent PTHL in patients who develop early renal dysfunction or have longstanding pre-transplant renal dysfunction.

This study suggested that there was a correlation between renal function and PTHL, which may be of great help in better understanding the pathogenesis of PTHL, and as much as possible, preventing its development.

This is a good retrospective study. There were some limitations in this study, but were reasonably explained by the authors. In my opinion, this study is original and it is acceptable for publication.