Targeting hepatitis B virus-associated nephropathy: efficacy and challenges of current antiviral treatments

Abstract

Hepatitis B virus (HBV) infection remains a major global health challenge, affecting approximately 296 million people and causing significant mortality annually. Despite vaccination efforts, HBV prevalence persists, particularly in low- and middle-income regions and endemic areas like China. HBV is closely associated with various kidney diseases, including acute kidney injury, chronic kidney disease, and glomerulonephritis, through mechanisms such as immune complex deposition, direct viral invasion, and chronic inflammation. Patients undergoing hemodialysis or kidney transplantation are at increased risk of HBV infection and reactivation, highlighting the need for effective preventive and therapeutic measures. This review examines the classification and clinical features of HBV-associated nephropathy, focusing on membranous nephropathy and membranoproliferative glomerulonephritis. It explores the pathogenesis, emphasizing immune complex deposition and podocyte apoptosis. Antiviral therapy, particularly with nucleos(t)ide analogs like entecavir and tenofovir (including TAF and TMF), demonstrates superior efficacy and safety compared to older agents such as lamivudine and adefovir. While interferon therapy offers benefits, its use is limited by adverse effects. Additionally, individualized treatment strategies for specific populations, including pregnant women and HIV co-infected patients, are crucial. Addressing HBV-associated nephropathy requires enhanced surveillance, timely antiviral intervention, and tailored therapeutic approaches to improve patient outcomes.

Graphical abstract

Introduction

Hepatitis B virus (HBV) infection represents a significant global public health challenge, affecting approximately 296 million individuals and causing an estimated 820,000 deaths annually [1]. Despite widespread vaccination efforts, infection rates remain notably high in low- and middle-income countries and in regions with endemic HBV prevalence [2, 3]. In China, the prevalence of hepatitis B surface antigen (HBsAg) in the general population is estimated to be around 6.1%, highlighting ongoing challenges in vaccination and infection control [4].

HBV infection is closely linked to a range of kidney diseases, including acute kidney injury (AKI) [5, 6], chronic kidney disease (CKD)[7, 8], and glomerulonephritis [9, 10]. HBV-induced kidney damage occurs through multiple mechanisms, including immune complex deposition [11], direct viral invasion [12], and chronic inflammation [13]. Chronic HBV infection is an independent risk factor for CKD, particularly in patients with advanced liver fibrosis, who are at significantly increased risk of developing new-onset CKD and end-stage renal disease (ESRD) [14]. Additionally, the deposition of HBV antigens exacerbates renal damage in IgA nephropathy, accelerating disease progression [15]. Among patients with HBV-associated acute-on-chronic liver failure (ACLF), the incidence of AKI is as high as 61%, significantly worsening prognosis [16]. Moreover, the synergistic effect of HBV with metabolic-associated fatty liver disease further elevates the risk of diabetes and CKD, adding to the burden on renal health [17].

Patients undergoing hemodialysis and kidney transplantation are at particularly high risk of HBV infection. The frequency of invasive procedures associated with hemodialysis leads to a markedly increased HBV infection rate compared to the general population [18]. For instance, in Ghana, the prevalence of HBsAg among hemodialysis patients is 7.7%, with an occult HBV infection rate of 7.3%. In Romania, the HBV infection rate among dialysis patients remained between 4.7 and 4.8% from 2015 to 2019 [19]. In Saudi Arabia, 3.77% of dialysis patients tested positive for HBsAg. These data indicate a heightened susceptibility to bloodborne pathogens during dialysis, necessitating focused preventive measures.

Kidney transplant recipients are also at elevated risk of HBV infection and reactivation due to long-term immunosuppressive therapy. For recipients of kidneys from HBV-positive donors, the risk of HBV reactivation is particularly high. Studies have shown that the rate of HBV reactivation among transplant recipients who did not receive antiviral prophylaxis is 12% [20]; whereas, no reactivation was observed in those who received prophylactic antiviral treatment, underscoring the importance of prophylaxis in reducing reactivation risk. The prolonged use of immunosuppressants weakens antiviral immunity, increasing the likelihood of HBV reactivation. Additionally, the use of selective costimulation blockers, such as belatacept, has been associated with a significantly increased risk of HBV reactivation, necessitating heightened monitoring and management [21].

Overall, the high prevalence of HBV infection among patients with kidney disease and its detrimental impact on renal function demand urgent attention. Enhanced surveillance and timely antiviral therapy are essential to improving patient outcomes.

Definition, classification, and clinical features of HBV-associated nephropathy

HBV-associated nephropathy represents a spectrum of kidney diseases caused by HBV infection, the most common of which is membranous nephropathy (MN) [22]. Other types include membranoproliferative glomerulonephritis (MPGN) and mesangial proliferative glomerulonephritis (MesPGN) [23, 24]. HBV-associated nephropathy is typically characterized by the deposition of immune complexes in the kidneys of patients with chronic HBV infection, resulting in glomerular inflammation and damage.

The classification of HBV-associated nephropathy is based on the type and pathological characteristics of glomerular lesions. MN is the most prevalent type, characterized by the deposition of immune complexes on the glomerular basement membrane, which leads to proteinuria [25]. Epidemiological data indicate that HBV-associated MN accounts for approximately 60–70% of HBV-associated nephropathy cases, particularly in adults [26]. MPGN accounts for nearly 30% of HBV-associated nephropathy cases [27] and is marked by mesangial cell and matrix proliferation accompanied by immune complex deposition [28]. This form often progresses rapidly, leading to renal insufficiency [29, 30]. MesPGN is relatively more common in children, usually presenting with mild proteinuria and microscopic hematuria [31]. While most pediatric patients with MesPGN have a favorable prognosis, some cases may progress to chronic kidney disease [32].

The clinical manifestations of HBV-associated nephropathy are diverse, with common symptoms including heavy proteinuria, microscopic hematuria, hypertension, and gradually declining renal function. Some patients may also present with liver-related symptoms, such as jaundice and hepatosplenomegaly [33]. Additionally, HBV infection is associated with other systemic complications that can further impact patient health. For instance, a study by Buonomo et al. (2018) highlighted a high prevalence of erectile dysfunction (ED) in patients with HBV-related chronic liver diseases [34]. This underscores the multifaceted impact of HBV infection on various aspects of patient well-being, beyond renal involvement. The prognosis of HBV-associated nephropathy depends on the specific pathological type and the degree of disease progression. Patients with MN generally have a favorable prognosis; while, those with MPGN have a more severe course, often leading to ESRD [35]. HBV-associated nephropathy significantly impacts both prognosis and quality of life, particularly for patients with concomitant severe liver disease, where dual impairment of renal and hepatic function poses a considerable therapeutic challenge. Therefore, early diagnosis and timely intervention are crucial for improving outcomes in these patients.

Pathogenesis of HBV-associated nephropathy

The pathogenesis of HBV-associated nephropathy involves several interrelated pathological processes. These include immune complex deposition, direct infection of podocytes and other renal cells, and abnormal immune activation. Different pathological types of HBV-GN show distinct characteristics and mechanisms that collectively lead to kidney damage and disease progression.

Immune complex deposition is a key mechanism of HBV-induced kidney damage [36]. HBV antigens (e.g., HBsAg, HBcAg) bind to host antibodies, forming immune complexes that deposit within the glomeruli [37]. This deposition causes various pathological changes. In MN, these complexes deposit on the subepithelial side of the glomerular basement membrane, leading to membrane thickening and proteinuria [38]. In MPGN, the complexes deposit in the mesangial area and the basement membrane, causing mesangial cell proliferation [39]. In MesPGN, the complexes deposit mainly in the mesangial region, leading to mild mesangial proliferation [40]. Complement activation is particularly significant in MPGN [41]. Elevated complement levels are closely associated with glomerular inflammation and damage [42].

HBV can also directly infect kidney cells, including podocytes. Podocytes express NTCP, the receptor for HBV entry, which makes them vulnerable to infection. After infection, podocytes undergo apoptosis and show reduced expression of cytoskeletal proteins, impairing their ability to proliferate and migrate [43]. HBsAg and HBcAg are predominantly found in renal cells, indicating that direct viral infection plays a crucial role [44]. High viral load is linked to worsening proteinuria and declining kidney function in patients.

Podocyte death, especially ferroptosis and pyroptosis, is central to HBV-associated nephropathy. The HBx protein of HBV activates STAT3, which induces ferroptosis in podocytes [45]. On the other hand, HBx upregulates the M-type phospholipase A2 receptor, which activates the ROS-NLRP3 signaling pathway, triggering pyroptosis [46]. These mechanisms lead to further podocyte injury and contribute to the progression of kidney damage.

Role of antiviral therapy in HBV-associated nephropathy

Antiviral therapy, by suppressing HBV replication, significantly reduces antigen production, thereby decreasing immune complex deposition and preventing further glomerular damage. Studies have shown that antiviral treatment reduces HBsAg levels by about 80% [47], lowers immune complex formation [48], and can reverse renal pathology in patients [49]. This highlights the essential role of antiviral therapy in preserving renal function and improving histopathological outcomes in HBV-associated nephropathy.

Nucleos(t)ide analogs

Entecavir (ETV)

Entecavir is a potent and highly selective HBV reverse transcriptase inhibitor widely used in the treatment of chronic hepatitis B (CHB) and its related nephropathies. Its efficacy is particularly notable in patients with HBV-associated nephropathy [50]. Studies have demonstrated that ETV treatment reduced 24 h urinary protein excretion. The total probability of partial proteinuria and complete remission at 24 and 52 weeks was 53.1 and 78.1%, respectively. A decrease in circulating HBV DNA was observed in all patients with active HBV replication [51]. Additionally, clinical trials have shown significant improvement in patients’ glomerular filtration rate (GFR) [52]. In patients with HBV-GN, ETV significantly slowed renal function decline and improved renal survival rates during a 36 month follow-up [53]. According to the 2024 World health organization (WHO) guidelines, ETV is recommended for patients requiring a high genetic barrier to resistance, particularly those with renal insufficiency or a risk of osteoporosis. The guidelines also highlight the safety and efficacy of ETV in children and adolescents, recommending it as a first-line treatment [54].

A key advantage of ETV is its low resistance rate, with resistance occurring in less than 1% of patients over 5 years [55]. This makes ETV a suitable option for long-term therapy, especially for patients requiring sustained viral suppression. Routine monitoring of HBV DNA levels and resistance mutations facilitates early detection of resistance, enabling timely adjustments to treatment. ETV’s low nephrotoxicity is an added benefit, making it particularly suitable for patients with chronic renal insufficiency. Most patients experience no significant deterioration in renal function, and adverse reactions are infrequent during long-term follow-up [56]. Clinical data indicate that fewer than 5% of patients report mild side effects, such as fatigue or nausea, with serum creatinine levels remaining stable within a 5% variation of baseline values [57]. These findings suggest that ETV provides both effective viral suppression and renal protection with a favorable safety profile.

Entecavir’s once-daily dosing regimen and excellent tolerability contribute to high patient adherence [58]. Studies indicate that adherence rates for ETV treatment reach 90.8%, significantly higher than the 83.9% observed with lamivudine [59].

For patients with renal impairment, dose adjustment of ETV is crucial to reduce the risk of drug accumulation. For those with an estimated glomerular filtration rate (eGFR) between 30 and 50 mL/min, dosing should be reduced to once every two days. Patients with eGFR below 10 mL/min who are not on dialysis should receive ETV twice weekly. In dialysis patients, the medication should be administered immediately post-dialysis to achieve optimal concentrations [60]. The WHO guidelines emphasize that dosage adjustments are necessary in patients with renal dysfunction to ensure treatment safety and efficacy.

Tenofovir and its novel formulations

Tenofovir disoproxil fumarate (TDF) is a potent nucleotide reverse transcriptase inhibitor widely used in the treatment of CHB, particularly in patients with HBV-associated nephropathy [61]. The 2024 WHO guidelines recommend tenofovir as a first-line therapy, especially for patients at risk of renal dysfunction or osteoporosis. Studies have shown that TDF can significantly reduce serum HBV DNA levels within 48 weeks of treatment and improve proteinuria [62].

Tenofovir has a high genetic barrier to resistance, with a resistance rate of less than 1% during long-term therapy, making it superior to lamivudine and other antiviral agents [63]. Although in vitro studies have identified mutations like rt181T/V and rtN236T that may affect tenofovir sensitivity, clinical evidence shows no significant resistance issues [64]. Long-term use of tenofovir, however, is associated with the risk of renal tubular injury, leading to increased serum creatinine and decreased serum phosphorus in some patients [65]. In a long-term follow-up study of 308 HBV patients treated within the United States Veterans Affairs system, TDF use led to an average eGFR decline of 4.6 mL/min, indicating a potential negative impact on renal function [66].

In addition to the traditional TDF, novel formulations such as tenofovir alafenamide (TAF) and tenofovir amibufenamide (TMF) have been developed to improve safety and tolerability. TAF is an improved formulation of tenofovir that achieves higher intracellular drug concentrations and lower plasma concentrations, reducing renal and bone toxicity [67].

TAF has emerged as a superior alternative to TDF for managing HBV-associated nephropathy, offering enhanced renal safety without compromising antiviral efficacy. A multi-center study reported significant HBV DNA suppression and improved eGFR in 313 chronic hepatitis B patients who switched to TAF from entecavir or nucleos(t)ide analog combination therapy [68]. Another study showed that in 176 CHB patients, switching to TAF resulted in undetectable HBV DNA levels in 75% of NA-naïve patients and significant renal function improvements in those with CKD [69]. Additionally, Hosaka et al. (2021) observed favorable long-term renal outcomes in 306 CHB patients switching to TAF, including increased eGFR in advanced CKD stages and stabilized renal function in milder cases [70]. The patients who received TAF showed only minimal declines in estimated glomerular filtration rate compared to greater declines with TDF, particularly at 12 weeks. Those receiving TAF also showed smaller mean percent declines in hip and spine BMD at 24 weeks [71].

TMF utilizes innovative ProTide technology and methylation strategies, which enhance its lipophilicity and plasma stability, thereby improving antiviral potency and safety [72]. A multi-center retrospective study showed that CHB patients treated with TMF achieved a virologic response rate of 53.57% at 24 weeks, comparable to TAF [73]. TMF also exhibited favorable outcomes regarding bone density and renal function safety, offering superior protection against bone density loss and maintaining stable renal function [74].

Tenofovir’s once-daily dosing regimen promotes high adherence [75]. Studies indicate adherence rates of 93.4% for TDF [76]. Patients switching from TDF to TAF or TMF have shown significant improvements in renal function and bone health, further enhancing adherence and quality of life [77].

Lamivudine(LAM), telbivudine (LdT), and clevudine

Lamivudine (LAM) was one of the earliest nucleoside analogs used in the treatment of hepatitis B [78]. It reduces viral replication by inhibiting HBV reverse transcriptase activity. Despite its efficacy in reducing viral load and improving clinical status, lamivudine’s high rate of resistance limits its utility in long-term use [79]. In a 3 year study, approximately 50% of patients developed resistance [80]. LAM has a favorable safety profile with few side effects, such as fatigue and mild gastrointestinal discomfort. It remains effective for short-term use in patients with low viral loads who require rapid viral suppression [81].

Telbivudine (LdT) is an oral nucleoside analog with potent HBV DNA inhibition [82]. In HBV-GN patients, telbivudine achieved a reduction in HBV DNA with serum HBeAg eliminated in some patients [83]. However, resistance rates increase to 25% after the second year of treatment, and some patients may develop muscle toxicity, such as elevated creatine kinase levels, necessitating close monitoring [84, 85].

Clevudine also demonstrates potent HBV inhibition, with lower resistance rates compared to LAM [86]. However, its use is limited by the occurrence of severe muscle toxicity during prolonged use, including myalgia and muscle weakness [87]. Thus, clevudine is generally reserved for patients who cannot tolerate other treatment options.

The high resistance rate of LAM is the primary limitation for its long-term use. The cumulative first-, second-, third-, fourth-, and fifth-year rates of virologic breakthrough during extended LAM therapy were 24%, 30%, 38%, 46%, and 54%, respectively [88]. Resistance is associated with viral rebound and exacerbation of liver and renal damage. Consequently, the 2024 WHO guidelines do not recommend LAM for long-term use. For patients with resistance, switching to tenofovir or ETV is typically required to maintain efficacy. Telbivudine also exhibits high resistance rates. It is mainly used for treatment-naïve patients who need rapid viral suppression over the short-term [89]. Due to the uncertainty in toxicity, clevudine is not recommended as a first-line treatment in the WHO guidelines.

Lamivudine’s once-daily dosing and good tolerability contribute to high patient adherence, although its high resistance rate limits its suitability for long-term use. Telbivudine also shows good adherence, but the development of resistance and muscle toxicity can negatively impact long-term adherence, especially if adverse effects occur. Clevudine, on the other hand, has lower adherence due to frequent monitoring requirements and significant muscle toxicity, which leads some patients to discontinue therapy.

Adefovir dipivoxil (ADV)

Adefovir dipivoxil (ADV) is a nucleotide analog commonly used in patients resistant to LAM [90]. Adefovir inhibits HBV reverse transcriptase, thereby reducing viral replication. In a randomized trial, the reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10(5) copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 [91]. In patients with LAM resistance, adefovir was effective in controlling viral load and reducing liver inflammation and fibrosis [92].

Adefovir has a relatively low resistance rate during the first two years of treatment (< 5%), but this rate increases to around 28% after 5 years [93]. The primary resistance mutations involve the rtN236T and rtA181V/T loci, which are associated with reduced sensitivity to adefovir [94]. In patients with resistance, switching to tenofovir or combination therapy with other antivirals is recommended. It’s worthy to emphasize caution in long-term adefovir use, particularly in patients with impaired renal function, and recommend dosage adjustments to mitigate nephrotoxicity [95]. Approximately 11% of patients exhibit some degree of renal function decline after two years of treatment [96].

Adefovir’s once-daily dosing regimen is convenient for patients, but the requirement for regular renal function monitoring poses a challenge, leading to reduced adherence for some individuals. Non-adherence was also found to be a significant cause of virologic breakthrough in patients receiving adefovir [97].

Interferon therapy

Interferon (IFN) therapy plays a limited role in the treatment of HBV-associated nephropathy. Interferons act by enhancing the host immune response to control HBV infection, offering some therapeutic potential for patients with HBV-GN [98]. The goal of interferon therapy is to suppress viral replication and stimulate the immune system to eliminate infected cells, potentially reducing immune complex deposition in the kidneys [99]. Some study has showed interferon and nucleoside analogs were equally effective at causing proteinuria remission and HBeAg clearance [100]. Peginterferon alfa-2b (Peg-IFN α-2b) has demonstrated superior efficacy over NAs in the treatment of CHB, particularly among patients with low levels of HBsAg. By week 24, the HBsAg clearance rate in the Peg-IFN α-2b group was notably 52.1%. However, due to poor overall tolerability, many patients discontinued treatment due to adverse effects [101]. Therefore, interferon is not recommended as a first-line treatment for patients with severe renal impairment, where the risks may outweigh potential benefits.

Interferons suppress HBV replication by activating the host immune system, which circumvents the resistance associated with direct antiviral agents, making them suitable for patients with resistance to nucleos(t)ide analogs. However, interferon therapy is accompanied by significant adverse effects, particularly in patients with HBV-associated nephropathy. These side effects include flu-like symptoms (e.g., fever, fatigue), hematological abnormalities (e.g., neutropenia, thrombocytopenia), and neuropsychiatric symptoms (e.g., depression, anxiety) [102]. For patients with significant renal impairment, the safety of interferon therapy is uncertain, necessitating careful consideration of the risk-to-benefit ratio [103]. Adherence to interferon therapy is generally low, primarily due to the significant impact of side effects on patients’ quality of life.

Comprehensive comparison of antiviral agents for HBV-associated nephropathy

In the treatment of HBV-associated nephropathy, nucleos(t)ide analogs (NAs) and interferons are the most commonly used antiviral agents. NAs include entecavir (ETV), tenofovir (TDF, TAF, TMF), lamivudine (LAM) and adefovir (ADV); whereas, interferons function by enhancing the host immune response to control HBV infection. A detailed comparison of these antiviral agents is presented in Table 1.

Table 1.

Comparison of antiviral drugs in the treatment of HBV-associated nephropathy

A DrugAntiviral efficacy ntiviral Eff y	iResistance	Major Side ResistanceMajor side effects Effects	Suitable PopulSuitable population ation	Special CoSpecial considerations nsiderations
High efficacy in reducing viral load and proteinuria	Low (<1% resistance over 5 years)	Mild (fatigue, nausea)	Chronic HBV patients, including those with renal insufficiency	Recommended for high genetic barrier to resistance and good renal safety.
Potent reduction in HBV DNA and proteinuria	Low resistance (<1%)	Renal tubular toxicity, bone mineral loss	Suitable for patients at risk of osteoporosis, not ideal for those with renal impairment	Requires close monitoring of renal function; not ideal for long-term use in renal-impaired patients.
Similar efficacy to TDF, with better renal and bone safety	Very low resistance	Minimal renal and bone toxicity	Suitable for long-term therapy, especially in patients with renal or bone health concerns	Preferred over TDF for better safety; particularly suitable for patients with chronic kidney disease.
Comparable efficacy to TAF, possibly superior in renal protection	Very low resistance	Minimal (similar to TAF)	Suitable for high-risk patients requiring better renal safety	Further reduced renal and bone toxicity; requires less frequent dose adjustments.
Effective in reducing viral load short-term	High (up to 70% over 5 years)	Generally well-tolerated (fatigue, GI symptoms)	Short-term use in low viral load patients needing rapid control	High resistance limits long-term use; often replaced by tenofovir or entecavir upon resistance.
Moderate efficacy in reducing viral load	High (15-20% by second year)	Muscle toxicity (elevated CK)	Initial therapy for treatment-naïve patients needing rapid suppression	Not recommended for long-term use due to resistance and toxicity concerns.
Potent reduction of viral load	Lower than lamivudine but muscle toxicity limits use	Severe muscle toxicity (myalgia, muscle weakness)	Reserved for patients intolerant to other therapies	Not recommended for long-term use; significant muscle toxicity risk.
Moderate efficacy, effective for lamivudine-resistant strains	Moderate (29% by 5 years)	Nephrotoxicity	Lamivudine-resistant patients	Requires dose adjustments in renal impairment; not a first-line choice due to nephrotoxicity.
Moderately effective in immune enhancement and viral suppression	No direct resistance	Flu-like symptoms, hematological and psychiatric side effects	Patients desiring to avoid long-term nucleos(t)ide analogs	Poor tolerance limits use; careful consideration required for patients with renal impairment.

This table provides a comprehensive comparison of various antiviral medications used to treat hepatitis B virus (HBV)-associated nephropathy. It details each drug’s antiviral efficacy, resistance rates, major side effects, suitable patient populations, and special considerations. The information aims to guide clinicians in selecting the most appropriate antiviral therapy based on individual patient needs and specific clinical scenarios

Among NAs, tenofovir (particularly TAF and TMF) and entecavir demonstrate superior virological suppression [104]. Studies have shown that TAF achieved a complete virological response rate of 82.2% within the first 48 weeks of treatment [105]; while, TMF has also demonstrated comparable virological response rates in real-world studies, with relatively minor effects on renal function. Resistance is a key consideration when selecting NAs. ETV, TAF, and TMF all have high genetic barriers to resistance, making them the preferred options for long-term HBV treatment due to their extremely low resistance rates. In contrast, LAM and adefovir exhibit weaker efficacy and are associated with a higher risk of treatment failure due to their low genetic barriers to resistance [106, 107]. LAM’s high resistance rate often necessitates frequent adjustments in the treatment regimen, which negatively affects adherence. Adefovir has gradually been replaced by safer tenofovir formulations due to its nephrotoxicity.

When comparing TAF, TDF, and ETV, all three demonstrate similar efficacy in terms of virological suppression (e.g., ALT normalization, HBV DNA suppression, and HBsAg clearance) [108]. However, significant differences exist in their long-term usage and safety profiles. ETV has a higher safety profile for patients with renal impairment and is well-suited for long-term use. ETV’s low incidence of side effects contributes to better patient adherence over time. TDF, while effective in reducing HBsAg levels, is associated with increased risks of nephrotoxicity during prolonged use [109]. As an improved formulation, TAF has gradually replaced TDF due to its superior safety. In comparison, TAF demonstrates better renal and bone safety than TDF, making it particularly suitable for patients requiring long-term treatment [110]. TMF, as a new formulation of tenofovir, combines strong antiviral potency with favorable renal and bone safety, making it a highly effective option, particularly for patients with high viral loads [111]. And TMF was developed with optimized metabolism and stability, which contributes to its lower resistance rates and improved clinical tolerability [112].

Interferons have advantages and disadvantages when compared to NAs. They achieve viral control through immunomodulation, thereby reducing immune complex formation and minimizing renal damage. For those with relatively preserved renal function and a strong immune status, interferon may be an appropriate treatment option, particularly for patients seeking to avoid long-term use of nucleos(t)ide analogs [113]. However, their effectiveness is influenced by individual patient variability, and their frequent and significant adverse effects limit widespread use. Mutations of HBV core gene also have been reported as being related to the failure of interferon treatment in chronic hepatitis B [114]. Moreover, their immunostimulatory effect may exacerbate pre-existing renal damage, necessitating careful consideration when using them in patients with compromised kidney function [115].

Individualized treatment for specific populations

Individualized treatment strategies for HBV-associated nephropathy must consider the unique characteristics and medical needs of each patient group. The management approach can vary significantly depending on factors such as age, comorbidities, viral load, and overall health status. Effective individualized treatment involves selecting the most appropriate antiviral therapy and adjusting it according to the specific risks and benefits relevant to different patient populations. Figure 1 provides a visual summary of treatment options for these specific populations.

Fig. 1.

Individualized treatment algorithm for HBV-associated nephropathy. TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide; ETV: Entecavir; HIV: Human immunodeficiency virus; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease

For pregnant women and pediatric patients, the use of different NAs demonstrates varied safety profiles and efficacy [116]. TDF and ETV are considered relatively safe for use during pregnancy and in children [117, 118]. Approximately 90% and 33.9% of the TDF-treated mothers had viral loads ≤ 2000 IU/mL after delivery and at 28 weeks postpartum, respectively [119]. ETV, due to its low nephrotoxicity, is also suitable for pregnant women requiring urgent antiviral therapy or for children intolerant to other medications [120]. LAM is relatively safe for short-term use during pregnancy but carry a high risk of resistance, necessitating a switch to more durable antiviral agents postpartum [121]. The use of telbivudine and clevudine is limited or not recommended in pregnancy and pediatrics due to their association with myotoxicity and neurotoxicity [122, 123]. Adefovir, due to its high nephrotoxicity risk, is generally not a first-line option, but it may be cautiously used when other alternatives are unavailable, with strict renal function monitoring [124].

For patients co-infected with HIV, TDF use is associated with a greater decline in estimated glomerular filtration rate (eGFR), particularly among West African patients, where an average annual decline of −1.08 mL/min/1.73 m² has been observed [125]. Patients with HBV and HIV co-infection face a higher risk of renal function deterioration [126]. TAF appears safer for these high-risk patients, showing improvements in bone mineral density and no significant decline in renal function [127].

Among patients with HBV-associated acute-on-chronic liver failure (HBV-ACLF), TAF has demonstrated superior outcomes compared to ETV in terms of transplant-free survival and renal function preservation. During a 48 week follow-up, transplant-free survival rates were significantly higher in the TAF group than in the ETV group (76.00% vs. 58.00%), with greater reductions in HBV DNA levels [128]. Additionally, TAF provides better renal safety compared to ETV in HBV-ACLF, helping maintain stable renal function while reducing the liver transplantation rate and mortality [129].

For patients on immunosuppressive therapy, ETV has shown good safety when combined with corticosteroids or biologic agents, effectively suppressing HBV replication without significantly increasing adverse event risks [130, 131]. TAF is also a safe choice for these patients. In liver transplant recipients, the combination of TAF with immunosuppressants (e.g., everolimus) has been shown to improve renal function and overall treatment outcomes compared to ETV alone [132]. For HBV-infected patients undergoing chemotherapy, TAF provides relatively better renal protection, particularly in those at high risk for AKI due to factors like hypoalbuminemia or cisplatin use, making TAF an ideal choice during chemotherapy [133].

Most cases of HBV-GN occur in children and present with serum HBsAg positivity [134]. Among the HBV-GN children, about 70% were genotype C [135, 136]. In antivirals, LAM was the first drug which was used to diminish viral load and considered effective in the third trimester of pregnancy and resulted in reduced risk of chronic hepatitis B in the child [137, 138]. LAM reverses advanced inflammation and fibrosis/cirrhosis in young CHB children [139]. Compared to LAM, TDF demonstrates greater efficacy. TDF monotherapy over 96 weeks produced a significantly stronger virological response than LAM in children. HBV DNA reduction (> 3 log₁₀ IU/mL) was achieved in 100% of the TDF group, compared to only 62.5% in the LAM group [140]. TAF offers a safer alternative to TDF for children with chronic hepatitis B (CHB), showing high antiviral efficacy with fewer adverse effects. Interferon/peg-IFN and ETV are also common treatment options. Initial peg-IFN therapy results in higher rates of HBsAg serological response (SR) but lower virological and biochemical response rates than ETV at week 48 [141–143]. Combination therapy with interferon and nNAs is more effective for viral suppression and serological response in CHB children compared to interferon monotherapy [144]. The WHO recommends ETV for children aged ≥ 2 years and TAF as an alternative option for adolescents aged ≥ 12 years.

By providing targeted therapeutic recommendations, these individualized strategies aim to enhance treatment efficacy while minimizing adverse effects in vulnerable populations.

Conclusion

HBV-associated nephropathy continues to pose significant challenges to public health and clinical management. Key biomedical hurdles include the persistence of renal complications despite effective antiviral suppression, limited options for resistant cases, and safety concerns in special populations such as pregnant women and those with renal impairment. Currently available therapies, particularly tenofovir alafenamide and entecavir, demonstrate robust efficacy in suppressing HBV replication and mitigating renal damage. However, gaps remain in treatment accessibility, resistance management, and optimization for vulnerable groups. Urgent advancements are required to develop sensitive diagnostic tools, novel antivirals with fewer side effects, and combination regimens tailored for high-risk populations. Beyond biomedical solutions, a collaborative effort involving healthcare providers, public health authorities, and policymakers is crucial to enhance HBV screening, expand treatment coverage, and improve adherence. Addressing these issues holistically can significantly reduce the burden of HBV-associated nephropathy and improve long-term patient outcomes.

Abbreviations

ACLF

Acute-on-chronic liver failure

ADV

Adefovir dipivoxil

AKI

Acute kidney injury

CHB

Chronic hepatitis B

CKD

Chronic kidney disease

eGFR

Estimated glomerular filtration rate

ETV

Entecavir

ESRD

End-stage renal disease

GN

Glomerulonephritis

HBcAg

Hepatitis B core antigen

HBsAg

Hepatitis B surface antigen

HBV

Hepatitis B virus

HIV

Human immunodeficiency virus

IFN

Interferon

LAM

Lamivudine

LdT

Telbivudine

MAFLD

Metabolic-associated fatty liver disease

MesPGN

Mesangial proliferative glomerulonephritis

MN

Membranous nephropathy

MPGN

Membranoproliferative glomerulonephritis

NA

Nucleos(t)ide analogs

NTCP

Sodium taurocholate cotransporting polypeptide

TAF

Tenofovir alafenamide

TDF

Tenofovir disoproxil fumarate

TMF

Tenofovir amibufenamide

WHO

World health organization

Author contributions

Y.H. and Y.Z. were involved in conceptualization. Investigation was conducted by Y.H. and Y.Z. Project administration was managed by W.J. Supervision was provided by W.J. Y.Z. assisted in visualization. Y.H. and Y.Z. contributed to writing—original draft. W.J. contributed to writing—review and editing.

Funding

This research was supported by grants from the National Natural Science Foundation of China [82370724], the Qingdao Key Health Discipline Development Fund and the Qingdao Key Clinical Specialty Elite Discipline project.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

Not applicable.