Serum total bilirubin levels and renal function prognosis in Chinese kidney transplant recipients during outpatient follow-up

doi:10.21203/rs.3.rs-4977015/v1

Objective

Renal function is critical in kidney transplant recipients, as it is a key indicator of graft health and patient prognosis. The present study aims to explore the prognostic value of serum total bilirubin levels in predicting renal function outcomes in this population.

Methods

We conducted a retrospective analysis of 264 stable kidney transplant recipients from the Second Affiliated Hospital of Guangxi Medical University. The study's primary endpoint was the development of chronic renal allograft dysfunction. Multiple linear regression analysis was used to evaluate whether total bilirubin and Cystatin C were independently related. Binary logistic regression analysis was performed using the lowest total bilirubin group as an outcome variable. The Kaplan-Meier (K-M) curve was plotted to describe the survival period. The relationship between serum total bilirubin and renal outcomes in renal transplant recipients was evaluated using multiple Cox regression analysis.

Results

Multiple linear regression analysis showed a negative correlation between total bilirubin and cystatin C(β=-0.924; p = 0.03). Our analysis revealed a significant negative correlation between serum total bilirubin and cystatin C levels, suggesting that higher bilirubin levels are associated with better renal function. Binary logistic regression analysis suggested a correlation between glomerular filtration rate and low total bilirubin levels (OR = 0.962, 95%CI = 0.937~0.988, p = 0.004). The K-M curve suggested that higher total bilirubin levels were associated with better survival outcomes (p = 0.003). Multiple Cox regression analysis demonstrated that high total bilirubin levels predicted better postoperative outcomes in kidney transplant recipients (HR, 0.468; 95CI, 0.235~0.931; p = 0.03). The Kaplan-Meier curve and Cox regression analysis further confirmed the protective role of higher bilirubin levels in post-transplant renal function.

Conclusions

The findings indicate that serum total bilirubin may serve as a prognostic biomarker for renal function in kidney transplant recipients, offering a potential tool for early identification of those at risk for renal insufficiency.

Kidney transplantation

Total bilirubin

Prognostic biomarker

Renal insufficiency

Assessment of renal function holds paramount importance in the clinical management of kidney transplant recipients, as it serves as a pivotal indicator of graft health and overall patient prognosis. Traditional markers such as serum creatinine, while integral to renal function evaluation, may not always reflect the nuances of early post-transplant renal function changes. The quest for more sensitive and specific biomarkers has led to the exploration of novel indicators, one of which is serum bilirubin.

Serum bilirubin, predominantly recognized for its role in the diagnosis of liver dysfunction and jaundice, has recently been identified to possess a spectrum of physiological functions that extend beyond hepatic health. It has been characterized by its anti-inflammatory, antioxidant, and immunomodulatory effects, which are crucial in the context of various pathological conditions[1, 2]. A growing body of evidence underscores the potential association between serum bilirubin levels and the risk of developing cardiovascular and cerebrovascular diseases, metabolic disorders, and autoimmune conditions[3–5].

Intriguingly, a modest reduction in serum bilirubin has been linked to an increased risk of renal function impairment, particularly in patients with hyperuricemia[6], and has been implicated in the progression of chronic kidney disease[7]. In the domain of renal transplantation, serum bilirubin levels have been observed to be significantly lower in recipients experiencing acute rejection episodes compared to those without rejection[8]. Furthermore, a decline in serum bilirubin has been correlated with late graft failure, suggesting a possible role in the long-term success of renal transplants[9]. Given the cost-effectiveness and accessibility of serum bilirubin measurement, its incorporation into routine clinical assessments could provide a valuable tool for the early identification of renal insufficiency in kidney transplant recipients.

This study aims to investigate the prognostic value of serum total bilirubin levels in predicting renal function outcomes in a cohort of stable kidney transplant recipients. By examining the correlation between serum total bilirubin and established renal function indicators, this research seeks to establish serum total bilirubin as a potential biomarker for renal function damage in kidney transplant recipients. The findings of this study may offer insights into the early detection and management of renal function decline post-transplantation, potentially improving graft survival and patient outcomes.

2.1 Study Population and Inclusion Criteria

We analysed RTRs who visited the outpatient department of organ transplantation of the Second Affiliated Hospital of Guangxi Medical University from January 2019 to August 2023. A total of 264 RTRs were included in the study. The follow-up outpatients included in the study did not have diabetic nephropathy, lupus nephritis, malignant diseases, liver related diseases, hematological diseases, coronary artery disease, chronic heart failure, infectious diseases or other diseases that might affect the detection of serum total bilirubin.

2.2 Definition of Stable Renal Function and Immunosuppressive Treatment

The definition of stable renal function is as follows: there has been no delayed recovery of transplanted kidney function, severe postoperative infection, rejection, diabetes or renal insufficiency within 6 months of follow-up. All recipients demonstrated negative panel reactivity post kidney transplantation, indicating a low level of pre-existing antibodies against the donor antigens. The vast majority of renal transplant recipients receive immunosuppressive treatment with tacrolimus, mycophenolate mofetil, and prednisone.

2.3 Tacrolimus Therapy and Blood Concentration Monitoring

All recipients of kidney transplantation commenced tacrolimus therapy immediately following surgery, administered orally twice daily. The dosage of tacrolimus was adjusted individually based on blood concentration levels to maintain a target range of 5–15 ng/mL.

2.4 Biochemical Parameters and GFR Calculation

During follow-up at 3 and 6 months after renal transplantation, the results of total bilirubin, alanine aminotransferase(ALT), and aspartate aminotransferase༈AST༉ were all within 1.5 times the normal values. This study was approved by the ethics committee of the Second Affiliated Hospital of Guangxi Medical University. After one month of renal transplantation, routine laboratory indicators were tested 1–2 times a month. All RTRs were tested with blood drawn after an overnight fast. Biochemical parameters included total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, total cholesterol, triglyceride, low-density lipoprotein༈LDL༉, high-density lipoprotein, urea, creatinine, uric acid, Cystatin C, and fasting blood glucose, were measured using a Roche automatic biochemical analyzer. Serum total bilirubin was detected using diazonium method. Glomerular filtration rate (GFR) was calculated using the following formula: GFR = 135×min(crea/k,1)^a×max(crea/k,1)^−0.544×min(cysc/0.8,1)^−0.323×max(cysc/0.8,1)^−0.778×0.996 1^age(female×0.963)[10].

2.5 Follow-up Protocol and Primary Clinical Endpoint

We divided patients into quartiles based on the average serum total bilirubin levels from 3 to 6 months after transplantation. Follow up starts at the 6th month after renal transplantation. The primary clinical endpoint was chronic allograft dysfunction. Chronic allograft dysfunction was defined as impaired graft function (eGFR < 60 ml/min/1.73m²), and lasted for more than 3 months. The deadline for follow-up of renal transplant recipients was to reach the study endpoint or the end of the study.

Data analysis was performed using SPSS version 22.0. We divided renal transplant recipients into four groups based on the quartile of serum total bilirubin concentration. Continuous variables are analyzed for normality using Kolmogorov–Smirnov test. Continuous variables of normal distribution are expressed as mean ± standard deviation. Non normally distributed continuous variables were expressed using the median (interquartile range). The differences in variables between different groups were analyzed using one-way analysis of variance or Kruskal–Wallis test. The correlation between continuous variables was analyzed using Spearman correlation analysis. The relationship between serum total bilirubin and other factors was analyzed by multiple linear regression analysis. Binary logistic regression analysis was used to evaluate the correlation between serum total bilirubin and other variables. Kaplan-Meier method was used to plot survival curves and describe survival period. Cox proportional hazards regression model was used to evaluate the relationship between baseline serum total bilirubin concentration and outcomes in renal transplant recipients. P < 0.05 was considered signifcant.

4.1 Median Follow-Up and Clinical Endpoints

The median follow-up period for kidney transplant recipients was 79 weeks. Fifty-eight renal transplant recipients reached the clinical endpoints, namely the development of chronic allograft dysfunction.

4.2 Baseline Characteristics and Bilirubin Correlations

The baseline characteristics of all RTRs based on serum total bilirubin quartile levels were shown in Table 1. Male RTRs had a higher proportion than female recipients. As the serum total bilirubin level increases, the levels of serum albumin, hemoglobin, ALT, AST, and GFR increase, while the levels of cystatin C decrease. There was a significant negative correlation between serum total bilirubin and cystatin C levels. Multiple linear regression showed an independent correlation between serum total bilirubin and cystatin C levels(β=-0.924; p = 0.03)(Table 2).

4.3 Tacrolimus Concentration and Dosage Variations

The concentration and dosage of tacrolimus in RTRs at months 1, 3 and 6 were shown in Table 3. In the first month following renal transplantation, the tacrolimus levels in the first quartile were lower than those in the third quartile.. There was no significant difference in the concentration and dosage of tacrolimus among different groups of total bilirubin levels at the 1st, 3rd, and 6th months after renal transplantation.

4.4 Risk Factors for Low Serum Bilirubin Levels

To confirm the risk factors associated with low serum total bilirubin levels, we conducted a multivariate logistic regression analysis using the lowest quartile of serum total bilirubin as the binary dependent variable. Multivariate analysis showed that gender, GFR, and hemoglobin were still associated with low serum total bilirubin(Table 4).

4.5 Survival Analysis and Graft Survival Rate

The survival analysis included all patients with complete follow-up data. Patients lost to follow-up for non-death reasons were censored at the time of their last available data point. We divided RTRs into two groups based on the quartile of serum total bilirubin: Q1 + Q2 and Q3 + Q4. Kaplan-Meier curve analysis showed that RTRs with high serum total bilirubin had better graft survival rate than those with low serum total bilirubin(p = 0.003)(Figure 1). Multivariate Cox regression confirmed that low serum total bilirubin group (Q1 + Q2) was independently associated with lower survival rate(HR, 0.468; 95CI, 0.235 ~ 0.931; p = 0.03)(Table 5).

Our study represents a pioneering effort in meticulously evaluating the prognostic value of serum total bilirubin levels in relation to renal function among kidney transplant recipients with stable graft function. It is crucial to emphasize the significant predictive potential of serum total bilirubin highlighted by our findings. We discovered that lower serum total bilirubin levels were linked to an unfavorable prognosis in renal transplant recipients, a particularly compelling finding given bilirubin's known anti-inflammatory and antioxidant properties. Unlike creatinine, which can be influenced by muscle mass and dietary intake, bilirubin levels offer a potentially more accurate and reliable reflection of renal function in this specific population. Our results are consistent with studies from East Asian countries that have found higher bilirubin levels to be associated with a reduced risk of renal failure and prevention of end-stage renal disease[11, 12], while low bilirubin is associated with an increased risk of renal insufficiency[6, 13]. However, our findings contrast with those from a previous study in an American population that did not find pre-transplantation bilirubin levels to be predictive for graft rejection or protective effects, suggesting a need for further investigation into the underlying reasons for this discrepancy. It may be attributed to genetic, environmental, or treatment protocol differences between populations[14]. It is important to note that while traditional methods of renal function evaluation, such as measuring creatinine and urea levels, are well-established, they may not capture the full spectrum of renal health, especially in the early post-transplant period. In contrast, serum bilirubin, as an emerging biomarker, could complement these traditional methods by providing additional insights into the renal function of RTRs. The use of serum bilirubin in conjunction with established markers may therefore offer a more comprehensive assessment of renal function, better equipping clinicians to monitor and manage the complex interplay between renal health and transplant outcomes.

Cystatin C, recognized for its endogenous consistency, serves as a reliable marker for GFR changes. We selected Cystatin C for its demonstrated reliability in capturing the nuances of renal function post-transplantation. Unlike creatinine, which can be influenced by muscle mass and dietary intake, Cystatin C provides a more reliable and accurate reflection of GFR, making it an ideal biomarker for our study's objectives. Cystatin C was also considered an inflammatory marker of various diseases. In recent years, studies have found that serum cystatin C is elevated in patients with inflammatory lung disease[15], arterial stiffness[16], hypertension[17], and coronary artery disease[18] without chronic kidney disease. The concentration of cystatin C might be directly related to inflammation and atherosclerosis, and one of the mechanisms related to cystatin C and cardiovascular risk might be caused by the correlation between inflammation and atherosclerosis[19]. Our findings reveal a robust negative correlation between serum total bilirubin and Cystatin C levels, underscoring the potential of serum total bilirubin as an early indicator of renal function alterations in transplant recipients. This correlation offers a novel perspective in post-transplant care.

From the moment of transplantation in all RTRs, there was persistent sub-clinical inflammation[20]. Alfonso M et al. found that RTR in a stable state still exhibit systemic low-grade inflammation[21]. They considered that after renal transplantation, C-reactive protein decreased to normal level from the 6th month, while the cytokine tumor necrosis factor–α(TNF-α)、IL-6 began to decline in the 6th months and increased significantly from the 12th month until the end of follow-up. While the underlying mechanisms for these observed correlations are not entirely elucidated within our study, we propose several hypotheses for future research to explore, including genetic predispositions, immunosuppressive drug interactions, and post-transplant lifestyle factors. Low-grade inflammation is an independent risk in all disease states[22]. In recipients of renal transplants, the persistence of low-grade inflammation is implicated in elevating the risk of cardiovascular events, thereby influencing overall mortality rates. The precise pathways linking inflammation to these outcomes, however, require further investigation[23]. In obese or elderly patients, bilirubin is negatively correlated with C-reactive protein and serum amyloid protein levels, indicating that elevated bilirubin may be beneficial for renal transplantation in these patients [24, 25].

Post-transplantation, a persistent imbalance exists between oxidative stress and the body's antioxidant defenses[26]. RTRs often exhibit heightened oxidative stress, which, although partially mitigated by an upregulation of antioxidant mechanisms, remains significantly higher than normal levels[27]. Even in cases where the graft functions within an acceptable range, it does not achieve the normal oxidative balance as seen in non-transplant populations[28]. This chronic elevation in oxidative stress can impact the functionality of the renal allograft, with levels of malondialdehyde increasing and glutathione peroxidase decreasing, potentially linking to post-transplant complications such as graft function delays, viral infections, and microalbuminuria[29]. Additionally, weight gain, observed in about 30% of RTRs, may have renal functional implications and could influence long-term graft survival and patient outcomes, necessitating further research[30].

Tacrolimus, predominantly metabolized in the liver via the cytochrome P450 enzyme system, may intersect with the metabolic pathways of bilirubin, potentially influencing serum bilirubin levels[31]. Our study observed no significant variation in tacrolimus concentrations between the third and sixth month post-transplantation. Within the population of stable RTRs, the administration of standard immunosuppressants, including cyclosporine and tacrolimus, has been noted to decrease renal blood flow, which may precipitate heightened oxidative stress[32–34]. Unconjugated bilirubin is posited to exert an antagonistic effect on endogenous vasoconstrictors, which could be advantageous in mitigating atherosclerotic diseases[35]. Consequently, this suggests a preventative role against cardiovascular diseases. The capacity of unconjugated bilirubin to shield against endothelial dysfunction post renal transplantation warrants further evaluation, given its potential implications for graft health and patient outcomes.

Bilirubin exerts immunomodulatory effects by dampening effector T cell responses, inhibiting the complement cascade, and fostering the expansion of regulatory T cells[36]. This regulatory role is crucial for maintaining immune homeostasis and may contribute to the prevention of transplant rejection. Additionally, bilirubin is hypothesized to be inversely associated with levels of inflammatory cytokines, such as TNF-α. Sonkar et al.'s study[37] demonstrated that healthy controls had the lowest TNF-α levels, whereas RTRs experiencing rejection episodes exhibited the highest levels, with stable RTRs showing intermediate levels. Notably, a significant surge in TNF-α was observed in RTRs with biopsy-confirmed acute rejection[38]. These findings collectively suggest that bilirubin could play a protective role in RTRs, potentially reducing the risk of rejection and promoting graft tolerance.

The initial months following kidney transplantation are critical for the early recovery and adaptation of the graft. During this period, renal function can be influenced by various factors, including the surgical procedure, anesthesia, and immunosuppressive medications. Moreover, early post-transplant complications such as acute rejection and infections pose significant risks to renal function[39]. By establishing a baseline period of 3 to 6 months in our study, we aimed to mitigate the impact of these short-term factors, thereby enabling a more accurate assessment of the kidney's long-term functional capacity. This approach allows for a clearer observation of the progression to chronic allograft dysfunction once the initial complications have been managed or resolved.

Bilirubin, recognized for its robust antioxidant properties, plays a pivotal role in safeguarding renal cells against the oxidative stress typically encountered post-transplant due to ischemia-reperfusion injury. Its immunosuppressive effects are instrumental in managing inflammatory responses and modulating the immune system, which is essential for averting rejection and fostering transplant tolerance. The upregulation of Heme Oxygenase-1, an enzyme linked to increased bilirubin production, may further bolster renal function and the overall health of the transplant[40]. As a hormone-like substance, bilirubin is postulated to influence a spectrum of cellular signaling pathways critical for maintaining homeostatic balance in the transplanted kidney. This includes lipid metabolism and energy utilization, which are vital for the organ's long-term functionality. Enhancing vascular function and augmenting nitric oxide bioavailability, bilirubin may improve perfusion within the transplanted kidney, thereby potentially preventing hypertension—a significant factor contributing to graft longevity. Its interaction with the peroxisome proliferator-activated receptor alpha (PPARα) suggests that bilirubin could also modulate lipid profiles, mitigating the risk of post-transplant metabolic complications that could impair kidney function. The therapeutic potential of bilirubin, particularly when delivered via nanoparticles directly to the transplant site, offers a promising avenue for localized protection and enhanced graft survival[41].

The current study, while providing valuable insights, is limited by its focus on a Chinese population. There is evidence to suggest that the association between serum total bilirubin levels and disease progression in RTRs may vary across different regions, possibly due to genetic, environmental, or other unidentified factors. Consequently, the generalizability of our findings is constrained. To address this limitation and to further validate the prognostic significance of serum total bilirubin, it is imperative to conduct multicenter, large-scale, and prospective studies with diverse populations. Our findings indicate a significant negative correlation between serum total bilirubin and cystatin C, and a positive correlation with GFR, suggesting that higher bilirubin levels may be associated with better renal outcomes. Importantly, low serum total bilirubin levels were linked to an unfavorable prognosis in RTRs, proposing a potential role for serum total bilirubin as a protective factor for renal function post-transplantation.

Acknowledgments

All authors have read the journal’s authorship statement and policy on disclosure of potential conflicts of interest.

This study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Clinical trial number: not applicable.

This study received the following funding support：Natural Science Foundation of Guangxi Zhuang Autonomous Region 2020GXNSFAA297234. This study also received the following funding support：self-funded scientifc research project of Guangxi Health Commission (Grant No. Z-A20220620).

Human Ethics and Consent to Participate declarations: not applicable.

Declaration of interests

The authors declare that there are no conflict of interests.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contribution

Q.H. was responsible for the overall study design and data analysis. H.W. contributed to the experimental design and interpretation of the results. L.L. and L.K. were primarily responsible for conducting experiments and managing data collection. X.L. was in charge of the research design and provided key guidance on the experimental process. W.Q. drafted the manuscript and coordinated revisions. All authors reviewed and approved the final manuscript

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Table 1. Baseline characteristics of renal transplant recipients based on the average serum total bilirubin levels from 3 to 6 months after transplantation.

	Quartile 1 （n=66）	Quartile 2（n=66）	Quartile 3（n=92）	Quartile 4（n=40）	p
Average serum total bilirubin,μmol/L	3.86±0.68	5.90±0.60	7.84±0.66	11.30±2.51	＜0.001
Gender，male/female	34/32	41/25	66/26	31/9	0.018
Age, years	36.22±12.08	38.27±9.88	41.34±11.61	40.13±11.16	0.059
Body mass index, kg/m2	20.34±6.77	24.98±35.55	21.75±5.83	20.38±6.56	0.402
Systolic pressure, mmHg	144.67±23.78	145.94±21.54	141.97±18.98	144.62±19.23	0.743
Diastolic pressure, mmHg	92.16±15.75	94.06±12.82	90.58±14.12	89.16±15.02	0.269
Time on dialysis (months)	31.09±21.26	28.75±25.63	30.98±28.20	26.97±23.69	0.405
Re-transplantation（yes/no）	No	No	No	No	—
Total protein, g/L	66.87±5.31	67.24±4.24	67.38±3.73	67.80±3.02	0.3
Albumin, g/L	43.76±2.87	44.66±2.41	45.55±2.31	46.00±2.06	＜0.001
AST, U/L	19.17±5.79	20.24±6.06	20.21±6.54	22.89±7.84	0.02
ALT, U/L	17.38±10.50	18.03±8.90	20.30±10.32	22.60±11.10	0.004
Total cholesterol, mmol/L	4.70±1.62	4.49±0.87	4.71±0.87	4.88±0.95	0.129
Triglyceride, mmol/L	1.87±0.86	1.78±0.77	1.74±0.71	1.89±0.88	0.86
HDL, mmol/L	1.33±0.36	1.38±0.42	1.40±0.43	1.48±0.37	0.355
LDL, mmol/L	2.84±1.26	2.63±0.66	2.85±0.72	2.94±0.80	0.064
Urea, mmol/L	9.35±3.23	8.42±2.30	8.46±2.49	8.13±2.45	0.082
Creatinine, μmol/L	138.64±47.52	131.33±32.54	136.18±46.32	131.87±38.15	0.893
Uric acid, μmol/L	369.02±78.37	372.21±71.17	369.34±68.79	384.29±76.26	0.660
Cystatin C, mg/L	1.83±0.47	1.60±0.38	1.62±0.47	1.52±0.36	＜0.001
Glomerular filtration rate, ml/min*1.73m2	43.93±16.76	49.69±13.34	49.08±13.34	51.45±14.45	0.006
Fasting blood glucose, mmol/L	5.20±0.86	5.21±1.21	5.23±0.93	5.35±0.85	0.264
Hemoglobin, g/L	108.04±15.40	117.82±21.76	121.52±29.02	136.06±15.82	＜0.001

AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, High density lipoprotein; LDL, Low density lipoprotein.

Table 2. Multiple linear regression analysis of serum bilirubin and laboratory indicators in renal transplant recipients based on the average serum total bilirubin levels from 3 to 6 months.

	Unstandardized coefficient		Standardized coefficient	t	P
	β	Standard error	Standardized coefficient	t	P
Gender	-0.949	0.408	-0.149	-2.325	0.021
Age	0.045	0.015	0.17	2.959	0.003
Cystatin C	-0.924	0.424	-0.134	-2.178	0.03
Albumin	0.208	0.079	0.163	2.635	0.009
Aspartate aminotransferase	0.036	0.036	0.076	1.004	0.316
Alanine aminotransferase	0.027	0.022	0.09	1.197	0.232
Hemoglobin	0.026	0.008	0.205	3.282	0.001
Constant	-5.362	4.157		-1.290	0.198

Table 3. Concentration and dosage of tacrolimus in renal transplant recipients.

	Quartile 1（n=66）	Quartile 2（n=66）	Quartile 3（n=92）	Quartile 4（n=40）	p
Tacrolimus level, ng/ml(1 month)	7.26±2.75	8.05±3.60	8.59±2.67	7.81±2.61	0.023
Tacrolimus dose, mg/day(1 month)	5.16±1.20	4.83±1.05	5.12±1.10	5.14±1.05	0.274
Tacrolimus level, ng/ml(3 month)	7.57±2.98	8.48±3.26	8.34±2.71	7.65±2.19	0.423
Tacrolimus dose, mg/day(3 month)	4.70±1.36	4.44±1.05	4.78±1.14	4.85±1.12	0.239
Tacrolimus level, ng/ml(6 month)	6.76±2.56	7.58±2.25	7.49±2.17	6.99±2.18	0.074
Tacrolimus dose, mg/day(6 month)	4.00±1.38	4.12±1.07	4.28±1.40	4.54±1.18	0.241

Table 4. Risk factors associated with the lowest serum bilirubin quartile.

Variable	Univariate		Multivariate
Variable	OR（95%CI）	P	OR（95%CI）	P
Gender	2.165（1.224～3.828）	0.005	0.446（0.199～0.999）	0.049
Age, years	1.030（1.008～1.053）	0.009	0.973（0.943～1.005）	0.116
Body mass index, kg/m2	0.980（0.939～1.023）	0.582
Systolic pressure, mmHg	0.994（0.988～1.016）	0.331
Diastolic pressure, mmHg	0.968（0.983～1.024）	0.105	1.000（0.977～1.024）	0.979
Total protein, g/L	1.026（0.908～1.036）	0.387
Albumin, g/L	0.778（0.689～0.878）	＜0.001	0.856（0.733～1.025）	0.055
AST,U/L	1.032（0.915～1.006）	0.104	0.948（0.878～1.023）	0.183
ALT,U/L	1.033（1.008～1.059）	0.010	0.979（0.930～1.029）	0.396
Total cholesterol,mmol/L	1.026（0.803～1.311）	0.253
Triglyceride, mmol/L	1.148（0.816～1.615）	0.689
HDL, mmol/L	0.607（0.295～1.252）	0.168	0.650（0.257～1.643）	0.362
LDL, mmol/L	1.054（0.775～1.433）	0.182	1.188（0.739～1.911）	0.477
Uric acid, μmol/L	0.999（0.995～1.003）	0.719
Fasting blood glucose, mmol/L	0.954（0.699～1.301	0.643
Glomerular filtration rate, ml/min*1.73m2	1.031（0.998～1.054）	0.074	0.962（0.937～0.988）	0.004
Hemoglobin, g/L	0.974（0.961～0.987）	＜0.001	0.984（0.969～0.999）	0.047

AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, High density lipoprotein; LDL, Low density lipoprotein.

Table 5. Multivariable Cox regression analysis of the relationship between serum total bilirubin concentrations and renal outcomes.

	Q1+Q2	Q3+Q4
	Q1+Q2	HR (95% CI)	p
Model 1	Reference	0.398（0.212～0.746）	0.004
Model 2	Reference	0.438（0.229～0.838）	0.013
Model 3	Reference	0.468（0.235～0.931）	0.03

Model 1, crude.

Model 2, adjusted for sex, age.

Model 3, adjusted for sex, age, BMI, diastolic pressure, glomerular filtration rate.

No competing interests reported.

Serum total bilirubin levels and renal function prognosis in Chinese kidney transplant recipients during outpatient follow-up

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Study Population and Inclusion Criteria

2.2 Definition of Stable Renal Function and Immunosuppressive Treatment

2.3 Tacrolimus Therapy and Blood Concentration Monitoring

2.4 Biochemical Parameters and GFR Calculation

2.5 Follow-up Protocol and Primary Clinical Endpoint

3. Statistical analysis

4. Results

4.1 Median Follow-Up and Clinical Endpoints

4.2 Baseline Characteristics and Bilirubin Correlations

4.3 Tacrolimus Concentration and Dosage Variations

4.4 Risk Factors for Low Serum Bilirubin Levels

4.5 Survival Analysis and Graft Survival Rate

5. Discussion

Declarations

References

Tables

Additional Declarations

Status:

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