Gao GF, Wang XY, Yu J. Rate of abnormal renal function index and related risk factors in patients with chronic hepatitis B. World J Gastroenterol 2025; 31(25): 105207 [DOI: 10.3748/wjg.v31.i25.105207]
Corresponding Author of This Article
Jiao Yu, Chief, MD, PhD, Department of Hepatology, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, No. 700 Moyu North Road, Jiading District, Shanghai 200433, China. yujiao7828@sina.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Guo-Feng Gao, Xiao-Yu Wang, Jiao Yu, Department of Hepatology, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200433, China
Author contributions: Yu J designed and conducted the study; Gao GF contributed to the analysis and wrote the paper; Wang XY collected the data; All authors have read and approved the final manuscript.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Shanghai Eastern Hepatobiliary Surgery Hospital (Approval No. EHBHKY2022-H006-P001).
Informed consent statement: The study protocol was in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. All patients provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Datasets are available from the corresponding author at yujiao7828@sina.com.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jiao Yu, Chief, MD, PhD, Department of Hepatology, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, No. 700 Moyu North Road, Jiading District, Shanghai 200433, China. yujiao7828@sina.com
Received: February 18, 2025 Revised: March 20, 2025 Accepted: May 8, 2025 Published online: July 7, 2025 Processing time: 136 Days and 1.2 Hours
Abstract
BACKGROUND
Patients with chronic hepatitis B (CHB) require long-term antiviral therapy. The effects of different antiviral drugs on kidney function are unclear. There is a lack of effective markers for monitoring early renal impairment.
AIM
To investigate the rate of abnormal renal function index and related potential hazards in patients with CHB.
METHODS
Clinical data of patients with CHB with urinary β2-microglobulin (β2-M) detection, including demographic characteristics, hepatitis B virus (HBV) DNA, serum liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin), serum renal function (urea nitrogen, creatinine), blood lipid index (high density lipoprotein, low density lipoprotein, cholesterol, triglyceride), liver imaging, and other routine tests were retrospectively collected. The normal level of urinary β2-M and estimated glomerular filtration rate (eGFR) is defined as < 0.173 mg/L and ≥ 90 mL/min/1.73 m2, retrospectively. The proportion of patients with abnormal renal function index and related risk factors were analyzed.
RESULTS
A total of 500 patients with CHB were enrolled; these patients were aged 44.7 ± 10.8 years, 67.2% (336/500) were male, 57.2% (286/500) were treated with antiviral drugs, and 52.2% (261/500) had an HBV-related family history. In total, 28.8% (144/500) of patients had fatty liver, 35.0% (175/500) had liver fibrosis, and 13.2% (66/500) had cirrhosis. The proportion of patients with eGFR < 90 mL/min/1.73 m2 was 43.2% (216/500), and the abnormal rate of urinary β2-M was 56.2% (281/500). There was no significant difference in the abnormal rate of urinary β2-M between the untreated group and the antiviral treated group (54.2% vs 57.7%; P= 0.25). The abnormal rate of β2-M after long-term entecavir treatment (more than 1 year) was 54.6% (89/163). In the treatment group, 56.4% (92/163) of patients with eGFR ≥ 90 mL/min/1.73 m2 had abnormal urinary β2-M.
CONCLUSION
In patients with CHB, a higher proportion had greater urinary β2-M levels than eGFR for renal injury. Male patients should pay more attention to renal function and use antiviral regimens with a renal safety profile.
Core Tip: Oral nucleos(t)ide analogues have been widely used for the treatment of chronic hepatitis B; however, their effects on kidney function remain inconclusive. In this study, no statistically significant differences in the effects of different antiviral drugs on renal function were observed. Urinary β2-microglobulin did not have a significant advantage over estimated glomerular filtration rate as an early warning of renal dysfunction. In addition, being male was an independent risk factor for renal impairment. Thus, men should pay more attention to the changes in renal function indicators when using antiviral drugs, which can provide a clear direction for clinical medication.
Citation: Gao GF, Wang XY, Yu J. Rate of abnormal renal function index and related risk factors in patients with chronic hepatitis B. World J Gastroenterol 2025; 31(25): 105207
Hepatitis B virus (HBV) affects approximately 262 million individuals globally and is responsible for about 900000 deaths annually, primarily due to complications such as cirrhosis and hepatocellular carcinoma (HCC)[1]. As HCC develops in about 25% of patients with CHB without antiviral treatment[2], the administration of antiviral treatment with oral nucleos(t)ide analog agents (NUCs) can reduce the risk of HCC by 50% in patients with CHB in the immune-active phase[3].
Unfortunately, NUCs are unable to eliminate covalent closed-loop DNA in hepatocytes infected with HBV, and complete clearance of hepatitis B surface antigen (HBsAg) in serum is difficult during NUC treatment. Accordingly, patients with CHB usually require lifelong treatment[4].
NUCs are safe and comparatively free of serious side effects. In fact, a fraction of subjects have encountered adverse effects after long-term use of NUCs, of which the most well-known were renal or bone damage caused by tenofovir disoproxil fumarate (TDF)[5].
Estimated glomerular filtration rate (GFR) is a traditional indicator of renal function and estimated GFR (eGFR) ≥ 90 mL/min/1.73 m2 is defined as normal kidney function[6]. In terms of nephrotoxicity due to TDF, tubular dysfunction is thought to precede a decline in GFR, indicating that renal tubular markers are more sensitive than eGFR calculated from serum creatinine when screening for TDF nephrotoxicity[7]. Low molecular weight proteins, such as α1-microglobulin (α1-M), β2-microglobulin (β2-M), retinol-binding protein and cystatin C, may be predictors of proximal tubular injury as they are freely filtered by the glomerulus and almost completely reabsorbed by proximal tubular cells[7,8]. Compared to these other proteins, β2-M in urine is a simple, reliable, and convenient biomarker[9].
Entecavir (ETV), with high antiviral efficacy and a high genetic barrier against viral resistance, is also a highly selective deoxyguanosine analogue[10]. Since ETV was approved by the United States Food and Drug Administration in 2005, it has been unanimously recommended by the Global Society of Hepatology as a first-line antiviral drug for the treatment of chronic HBV infection, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease[11,12].
Based on reports, approximately 73% of oral ETV is eliminated from urine in a constant form. The renal clearance rate of ETV is independent of dosage, ranging from 360 mL/min/1.73 m2 to 471 mL/min/1.73 m2 in healthy volunteers, which is much higher than the GFR of 120 mL/min/1.73 m2 to 130 mL/min/1.73 m2 for healthy individuals, indicating that tubular secretion is the main portion of ETV urinary excretion[13,14]. Therefore, based on relevant research, it is speculated that some transport proteins expressed on proximal tubular cells may be involved in the tubular secretion of ETV[15]. Although ETV showed excellent inhibition of HBV replication with no significant adverse events[16], monitoring of ETV-related toxicity, especially renal toxicity, is recommended during long-term treatment[17]. Accumulation of ETV in renal cells mediated by transporters can cause potential adverse reactions during long-term administration[15]. Long-term exposure to certain antiretroviral drugs can regulate the expression and activity of several drug transporters that deal not only with drugs but also with physiological endogenous substances[18].
In addition, due to a lack of data, different liver societies have nonuniform recommendations for the prescription of ETV, TDF, or another TFV-based agent tenofovir alafenamide (TAF). The EASL CHB guideline recommends using ETV and TAF instead of TDF in patients with high-risk factors, such as age over 60 years, osteopathy or kidney changes demonstrated by eGFR less than 60 mL/min/1.73 m2, proteinuria, hypophosphatemia and hemodialysis[11]. However, these guidelines do not explicitly favor ETV or TDF in light of the potential long-term hazard of renal and bone complications[12,19].
Due to the fact that antiviral therapy for HBV-infected individuals is usually lifelong and owing to increasing age and comorbidities of the population[20,21], further investigation is needed to determine the extended renal effects of NUCs in different real-world populations of Chinese patients with CHB.
Data concerning the utility of β2-M in the early prediction of NUC-relevant renal tubular malfunction in individuals with CHB under NUCs treatment are scare. The most recent research was based on the evaluation of urinary β2-M, with other renal function indices in the early prediction of NUC-relevant renal tubular malfunction in CHB patients receiving oral drug treatment.
MATERIALS AND METHODS
Study design
This cross-sectional study included consenting chronic HBV-infected populations who were followed at Shanghai Eastern Hepatobiliary Surgery Hospital Outpatient Hepatology Clinic (Shanghai, China) between June 2022 and May 2023. The protocol and informed consent were approved by the Institutional Clinical Research Ethics Committee in the hospital.
Patients with CHB were identified through a clinic or hospital registry. All patient charts were reviewed to confirm the diagnosis of CHB (HBsAg seropositivity and/or HBV DNA positive for more than 6 months), and history of treatment with NUCs and relevant demographic and laboratory data were collected using a uniform structured data framework and a uniform definition of data variables. Patients received oral NUC(s) during outpatient visits and follow-up according to the guidelines for the prevention and treatment of CHB[22]. The TAF group received oral TAF 25 mg, once daily; the TDF group received oral TDF 300 mg, once daily; the ETV group received oral ETV 0.5 mg, once daily. The NUC(s) switch group was converted from oral ETV or TDF to oral TAF; the other groups were treated with antiviral regimens other than those listed above. Data storage, quality control, and database management were implemented at Shanghai Eastern Hepatobiliary Surgery Hospital (Shanghai, China).
Patients who were initiated on and maintained on any NUCs for ≥ 12 months or untreated were included. The indication for NUCs followed the recommendations of the Chinese CHB guidelines at the time of treatment.
Patients who were co-infected with hepatitis C virus, hepatitis D virus, and human immunodeficiency virus, had a history of bone marrow or any other solid organ transplantation, chronic or severe immunosuppression, including chemotherapy and biologics, and had concomitant liver diseases (e.g., autoimmune hepatitis, primary biliary cholecystitis, Wilson's disease, hemochromatosis), α-1-antitrypsin deficiency, or known malignant tumors within 5 years of NUCs treatment were excluded. A flow chart of the study design and patient selection is shown in Figure 1.
Figure 1 Flow chart of the study design and patient flow selection.
HBV: Hepatitis B virus.
Clinical and laboratory data
Demographic data and related risk factor data were collected. The data included ethnicity, sex, age, family history of cirrhosis, and HCC.
Fibrosis, cirrhosis, HCC, and fatty liver were diagnosed by histology, instantaneous elastography, serum fiber tests, and imaging evidence of nodular liver, splenomegaly, or other portal hypertension disorders such as thrombocytopenia, ascites, varicose veins, or encephalopathy.
Routine serum chemistry for creatinine, and liver function tests were assessed using an autoanalyzer. HBV DNA testing was performed using the Hepatitis B Virus Nucleic Acid Quantitative Detection Kit (PCR-fluorescent probe method) (Shanghai Kehua Bio-engineering Co., Ltd., Shanghai, China). The lower detection limit of the HBV DNA assay is 50 IU/mL and undetectable is defined as less than the lower detection limit. β2-M testing was performed using N Latex β2-M (SIEMENS Healthineers, Forchheim, Germany).
Statistical analyses
Categorical variables (e.g., abnormal rate of β2-GM, sex, presence of comorbidities, cirrhosis) are expressed as a percentage, and untreated patients and those receiving NUCs were compared using the χ2 test. Continuous variables are expressed as the mean and standard deviation or range and quartile range.
For continuous variables, the unpaired Student's t-test or Mann Whitney U-test was performed on the data based on distribution (analysis of variance and Kruskal Wallis test for comparisons between two or more groups) and non-continuous variables using the χ2 test and Fisher's exact test.
Two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics v21 (Armonk, NY, United States).
RESULTS
Overall study cohort characteristics and renal outcomes
In total, 662 subjects were screened and 500 individuals with HBV infection were enrolled based on the inclusion and exclusion criteria (Figure 1). The mean age was 44.7 ± 10.8 years, and 67.2% (336/500) of patients were male. By analyzing the patients' relevant clinical data and answers to questions, all patients showed good clinical compliance. Among them, 214 (42.8%) patients were treatment-naïve (TN) with no HBV antiviral regimens (TN group) and 286 (57.2%) patients were treatment-experienced (TE) with any NUCs (TE group). The baseline characteristics in the two groups are shown in Table 1. In total, 56.2% (281/500) of the overall cohort had abnormal β2-M, 54.2% (116/214) in the TN group and 57.7% (165/286) in the TE group.
Table 1 Baseline characteristics of patients with chronic hepatitis B in the entire cohort.
TN group (n = 214)
TE group (n = 286)
P value
Patient characteristics
Age (years)
43.19 ± 10.75
43.47 ± 10.71
0.77
Male, %
58.4
73.8
< 0.05
Family history, %
48.6
54.9
0.10
Hypertension, %
5.1
5.6
0.50
Diabetes, %
4.7
3.8
0.41
Fatty liver, %
35.0
24.1
< 0.05
Fibrosis, %
40.7
30.8
< 0.05
Cirrhosis, %
5.6
18.9
< 0.05
HCC, %
0
1.7
0.06
Laboratory measurements
ALT, U/L
52.28 ± 108.40
29.12 ± 23.20
< 0.05
AST, U/L
34.73 ± 15.21
24.73 ± 47.77
< 0.05
Total bilirubin, μmol/L
13.49 ± 7.06
14.65 ± 8.70
0.11
Direct bilirubin, μmol/L
5.2 ± 3.29
5.52 ± 3.41
0.31
Blood urea nitrogen, mmol/L
4.59 ± 1.18
4.85 ± 1.14
< 0.05
eGFR, mL/min
94.41 ± 16.97
94.10 ± 16.05
0.83
Cholesterol, mmol/L
4.62 ± 0.93
4.29 ± 0.91
< 0.05
Triglyceride, mmol/L
1.28 ± 1.05
1.25 ± 0.97
0.77
High-density lipoprotein, mmol/L
1.40 ± 0.36
1.28 ± 0.34
< 0.05
Low-density lipoprotein, mmol/L
2.94 ± 0.86
2.72 ± 0.80
< 0.05
Abnormal β2-MG, %
54.2
57.7
0.25
TE group
In the TE cohort, 121 patients had normal urinary β2-M and 165 had abnormal urinary β2-M (Table 2). The percentage of males was 80% (132/165) in the abnormal group compared to 65.3% (79/121) in the normal group, the difference of 14.7% was statistically significantly different (P < 0.05). The mean alanine aminotransferase (ALT) level was 31.6 U/L in the abnormal group and 25.74 U/L in the normal group, and the difference was statistically significant (P < 0.05). In addition, the differences in total bilirubin and high density lipoprotein in the two groups were also significant (P < 0.05).
Table 2 Characteristics of β2 microglobulin normal and abnormal groups in treatment-experienced patients with any nucleos(t)ide.
Patient characteristics
Normal β2-MG (n = 121)
Abnormal β2-MG (n = 165)
P value
Age (years)
43.63 ± 10.88
43.36 ± 10.63
0.83
Male, %
65.3
80
< 0.05
Family history, %
52.1
57.0
0.53
Hypertension, %
5.8
5.5
0.90
Diabetes, %
5.0
3.0
0.40
Fatty liver, %
22.3
25.5
0.64
Fibrosis, %
30.6
30.9
1.00
Cirrhosis, %
18.2
19.4
0.92
HCC, %
1.7
1.8
0.92
HBV DNA-positive, %
15.8
14.6
0.91
ALT, U/L
25.74 ± 22.26
31.6 ± 23.62
< 0.05
AST, U/L
23.33 ± 9.86
25.75 ± 18.12
0.18
Total bilirubin, μmol/L
13.38 ± 5.72
15.59 ± 10.26
< 0.05
Direct bilirubin, μmol/L
5.08 ± 1.90
5.86 ± 4.16
0.06
Blood urea nitrogen, mmol/L
4.74 ± 1.05
4.94 ± 1.20
0.14
eGFR, mL/min
96.06 ± 16.38
92.66 ± 15.70
0.08
Cholesterol, mmol/L
4.30 ± 0.91
4.28 ± 0.91
0.87
Triglyceride, mmol/L
1.16 ± 0.71
1.31 ± 1.13
0.18
High-density lipoprotein, mmol/L
1.33 ± 0.35
1.25 ± 0.32
< 0.05
Low-density lipoprotein, mmol/L
2.75 ± 0.80
2.70 ± 0.80
0.64
Duration of NUC treatment (years)
4.25 ± 3.53
4.30 ± 3.28
0.90
Subgroup stratification analysis was performed on the TE cohort (Table 3). The abnormal rates of β2-M among different age groups, NUCs, duration of treatment and HBV DNA were not statistically significant. Compared with the female group, the abnormal rate of β2-M in the male group was numerically higher (44.0% vs 62.6%), and the difference was statistically significant (P < 0.05).
Table 3 Abnormal rate of urinary β2 microglobulin in different subgroups of treatment-experienced patients with any nucleos(t)ide.
Abnormal rate of β2-MG, %
P value
Age
> 65 years
50.0 (5/10)
0.62
≤ 65 years
58.0 (160/276)
Sex
Male
62.6 (132/211)
< 0.05
Female
44.0 (33/75)
NUCs
ETV
54.6 (89/163)
0.47
TDF
46.7 (7/15)
TAF
60.5 (26/43)
NUC switch
66.7 (40/60)
Others
60.0 (3/5)
Duration of NUC treatment
≤ 2 years
58.3 (60/103)
0.97
2-5 years
56.8 (63/111)
≥ 5 years
58.3 (42/72)
HBV DNA
Positive
55.8 (24/43)
0.87
Negative
58.1 (140/241)
In the TE group, 56.4% (92/163) of patients with abnormal urinary β2-M had an eGFR > 90 mL/min/1.73 m2 (Table 4).
Table 4 Correlation between estimated glomerular filtration rate and urinary β2 microglobulin.
Normal β2-MG
Abnormal β2-MG
Total
eGFR > 90 mL/min
71
92
163
eGFR ≤ 90 mL/min
50
73
123
Total
121
165
286
TN group
In the TN cohort, 98 patients had normal urinary β2-M and 116 had abnormal urinary β2-M (Table 5). The percentage of males was 65.5% (76/116) in the abnormal group compared to 50.0% (49/98) in the normal group, the difference of 15.5% was statistically significant (P < 0.05). The mean ALT level was 63.71 U/L in the abnormal group and 38.76 U/L in the normal group, and the difference was statistically significant (P < 0.05). The level of aspartate aminotransferase (AST) was also significantly different between the two groups (40.46 U/L vs 27.95 U/L, P < 0.05). In addition, the level of triglyceride between the two groups was also significantly different (P < 0.05).
Table 5 Characteristics of β2 microglobulin normal and abnormal groups in treatment-naive patients with any hepatitis B virus antiviral regimen.
Patient characteristics
Normal β2-MG (n = 98)
Abnormal β2-MG (n = 116)
P value
Age (years)
43.00 ± 10.96
43.34 ± 10.60
0.926
Male, %
50.0
65.5
0.026
Family history, %
53.1
44.8
0.272
Hypertension, %
4.1
6.0
0.555
Diabetes, %
2.0
6.9
0.114
Fatty liver, %
28.6
40.5
0.084
Fibrosis, %
38.8
42.2
0.676
Cirrhosis, %
4.1
6.9
0.553
ALT, U/L
38.76 ± 73.39
63.71 ± 130.14
0.017
AST, U/L
27.95 ± 23.95
40.46 ± 60.59
0.002
Total bilirubin, μmol/L
13.11 ± 6.25
13.81 ± 7.70
0.561
Direct bilirubin, μmol/L
5.01 ± 2.32
5.40 ± 3.92
0.505
Blood urea nitrogen, mmol/L
4.45 ± 1.12
4.71 ± 1.22
0.733
eGFR, mL/min
96.92 ± 18.05
92.28 ± 15.76
0.181
Cholesterol, mmol/L
4.52 ± 0.95
4.71 ± 0.90
0.540
Triglyceride, mmol/L
1.15 ± 0.53
1.3779 ± 1.33
0.008
High-density lipoprotein, mmol/L
1.41 ± 0.36
1.39 ± 0.37
0.669
Low-density lipoprotein, mmol/L
2.88 ± 0.91
2.99 ± 0.81
0.880
Subgroup stratification analysis was performed on the TN cohort (Table 6). The abnormal rates of β2-M among different age groups and HBV DNA were not statistically significant. Compared with the female group, the abnormal rate of β2-M in the male group was also numerically higher (44.9% vs 60.8%) and the difference was statistically significant (P < 0.05).
Table 6 Abnormal rate of urinary β2 microglobulin in different subgroups of treatment-naive patients with any hepatitis B virus antiviral regimen.
Abnormal rate of β2-MG, %
P value
Age
> 65 years
60.0 (3/5)
0.579
≤ 65 years
54.1 (113/209)
Sex
Male
60.8 (76/125)
< 0.026
Female
44.9 (40/89)
HBV DNA
Positive
55.7 (98/176)
0.364
Negative
45.9 (17/37)
In the TN group, 51.2% (62/121) of patients with abnormal urinary β2-M had an eGFR > 90 mL/min/1.73 m2 (Table 7).
Table 7 Correlation between estimated glomerular filtration rate and urinary β2 microglobulin.
Number
Normal β2-MG
Abnormal β2-MG
Total
eGFR > 90 mL/min
59
62
121
eGFR ≤ 90 mL/min
39
54
93
Total
98
116
214
DISCUSSION
Compared to the general population, renal damage is more common in individuals infected with HBV[23-25]. Compared with normal subjects, untreated CHB is a hazardous factor for chronic kidney disease, and individuals with CHB have a higher risk of developing kidney disease[26], as well as end-stage renal disease[27]. CHB is independently associated with early mortality due to various diseases, including kidney disease, compared to uninfected individuals[28].
Persistent infection with HBV may contribute to HBV-related glomerulonephritis. The presence of HBV-DNA, as well as HBV-RNA, in renal tubular epithelial cells suggests direct virus-induced injury. Proinflammatory cytokines and HBV X protein synergistically enhance tumor necrosis factor-related apoptosis-inducing ligand-induced renal tubule cell apoptosis through upregulation of death receptor 4[29]. Our study showed that in individuals with CHB without antiviral treatment, the levels of ALT and AST were significantly higher than those in patients receiving antiviral treatment, indicating that the patients with CHB were in the active stage of disease, thus the rate of abnormal urinary β2-M was increased. Therefore, individuals infected with HBV should actively receive antiviral regimens to reduce the occurrence of extrahepatic complications, such as kidney damage.
NUCs are generally considered safe and relatively free of serious side effects in clinical practice[30]. However, tubular dysfunction has been observed both in clinical studies and in the real world in patients with CHB receiving NUC therapy, especially with ADV and TDF[5]. After 6 months of treatment with TDF, more than half of subjects showed increased urinary β2-M, which is a sensitive marker for renal tubular disorders[31]. With the increase in life expectancy of HBV-infected populations, the long-term adverse effects of antiviral regimens are cumulatively apparent[32]. As a result, the management of tubular dysfunction that may occur during treatment has become a crucial problem in the management of individuals with CHB receiving NUC regimens. Our study showed that the HBV inhibition rate in patients with CHB receiving antiviral treatment was 84.2%, and liver function was mostly restored to normal, while long-term use of NUCs also resulted in a high proportion of urinary β2-M abnormalities. In addition, we also found that male patients who received antiviral therapy for a long period were more likely to have renal function impairment, and even in the absence of antiviral therapy, men were at high risk of renal function impairment. No differences in the rates of abnormal urinary β2-M were found among different drugs and duration of treatment, possibly due to the small sample size.
Despite severe damage to the proximal renal tubules, plasma creatinine levels can still be maintained within the normal range[33]. Therefore, routine monitoring of renal indicators cannot detect early damage in renal tubular function. Fortunately, research has found that some low molecular weight proteins in urine can be used as markers to detect nephrotoxicity[34]. Our study found that the median eGFR value was above 90 ml/min/1.73 m2 in both the TN and TE groups, indicating less glomerular damage in these patients.
β2-M, a low molecular weight protein, present in the plasma of healthy individuals, is freely filtered by normal glomeruli and then almost completely reabsorbed and metabolized by proximal tubular cells[35]. Patients with renal tubulointerstitial damage may experience elevated levels of urinary β2-M[36,37]. β2-M is widely excreted in the urine of patients with renal tubulointerstitial disease, and is therefore considered a sensitive indicator for the early detection of tubular dysfunction[38,39]. In our study, β2-M was used to detect early proximal tubular injury. In a study that examined the detection of proximal tubule lesions caused by TDF, this indicator was shown to have better reliability and sensitivity than other urinary biomarkers[40]. In the present study, it was found that in both TN and TE patients with eGFR >90 mL/min/1.73 m2, the abnormal rate of urinary β2-M exceeded one half. In clinical practice, for patients with normal eGFR, we still need to be alert to the possibility of renal tubular injury, strengthen detection and monitoring, and choose antiviral drugs with a better renal safety profile to slow down or reverse renal tubular injury deterioration as much as possible.
This study had some limitations. First, due to the retrospective nature of this cohort study conducted at a single center, the sample size was small. Future multicenter trials with larger sample sizes are needed to further validate these results. Second, there was no information on urinary β2-M excretion over 24 hours in clinical trials; instead, a spot urine sample was tested for urinary β2-M. Third, due to data limitations, other biomarkers such as α1-M and retinol-binding protein were not examined and the analyses were not adjusted for other confounders. Finally, we recognize that this was a cross-sectional study, and the dynamic changes in β2-M during treatment were not monitored; thus, further studies are required to address this issue.
CONCLUSION
In this study, we demonstrated that urinary β2-M has greater diagnostic efficacy than the blood indicator (eGFR) for renal injury in patients with CHB. Male patients with CHB need to pay more attention to monitoring renal function and use antiviral regimens with a good renal safety profile.
ACKNOWLEDGEMENTS
We are grateful to all participants, especially the study members. We are also obliged to the sample testers, who performed measurements of the urinary kidney injury markers.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade C, Grade C
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade C, Grade C
P-Reviewer: Kawachi S; Risaliti M S-Editor: Lin C L-Editor: Filipodia P-Editor: Yu HG
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