Hepatitis B and chronic kidney disease: Bench to bedside

Abstract

Chronic kidney disease (CKD) has an intricate relationship with hepatitis B virus (HBV) due to impaired immune status and repeated risk for HBV exposure in people with CKD. Extensive discussion is required on issues related to disease burden, progression of acute HBV infection to chronic infection, impaired immune response to the hepatitis B vaccine, optimal vaccination schedules and strategies, etc. In this review, we attempted to summarize the updated existing knowledge on these topics. In addition, the implication of HBV in the pathogenesis of glomerular disease is also discussed. This review extensively focused on issues related to hepatitis B vaccine induced immune response in CKD patients—serological and cell-mediated immune responses to the vaccine, with particular emphasis on effect of CKD stages on vaccine response, newer types of hepatitis B vaccines for non-responders, revaccination strategies, and the durability of vaccine-induced immunity. We also discussed the literature on risk of HBV transmission following organ from hepatitis B surface antigen (HBsAg)-positive donors, along with perioperative management when the donor is HBsAg-positive but the recipient is HBsAg-negative.

Key Words: Hepatitis B; Chronic kidney disease; Vaccination; Dialysis; Renal transplant

Core Tip: Hepatitis B virus (HBV) infection is prevalent in chronic kidney disease (CKD) patients, particularly those on hemodialysis. Vaccination against hepatitis B is recommended for all those with CKD. Highly effective oral antiviral drugs with a strong barrier to resistance are available for HBV treatment but they require dose adjustment based on a patients' creatinine clearance. Given the ever-increasing number of patients with CKD and HBV, it is crucial to raise awareness regarding its modes of transmission, prevention strategies, and available treatment modalities.

INTRODUCTION

Hepatitis B virus (HBV) infection is a global public health problem, affecting over 316 million people[1]. HBV infection is a risk factor to develop chronic kidney disease (CKD)[2-4]. People with CKD, in particular those on maintenance hemodialysis (MHD), have a high prevalence of HBV than the general population[5]. HBV seroprevalence, as measured by hepatitis B surface antigen (HBsAg) seropositive status, in MHD patients ranges from 2%-20% and largely depends upon the country, dialysis methods, and infection control measures taken in dialysis unit[5]. The burden of HBV in CKD populations is greater in endemic regions such as Sub-Saharan Africa and Southeast Asia. In India, up to 10% of MHD patients are HBsAg reactive[6]. Nosocomial transmission, caused by incomplete adherence to standard and dialysis-specific infection control precautions, leads to frequent HBV infections among those on MHD[7]. This review summarized the mechanisms of HBV-related kidney diseases, the clinical implications of HBV infection in people with CKD, the duration and durability of immune response to the hepatitis B vaccine, and the current understanding of the relationship between HBV and CKD.

HEPATITIS B-RELATED KIDNEY DISEASE

Liver and kidneys are the organs which frequently communicate through various physiological and pathological processes[8]. Disorders in one organ can affect the other. HBV infection can directly or indirectly predisposes for a range of kidney diseases, and vice versa[9]. The links between these organs are highlighted by the joint statement from academic societies on liver and kidney diseases[10]. Renal injury or disorders in individuals with HBV infection can occur during chronic hepatitis B, even without cirrhosis, due to antiviral treatments for HBV, or as a result of cirrhosis[3] (Table 1). Hepatitis B-related glomerular disease is more common in children than adults and in men than women[11].

Table 1 Common renal diseases/conditions associated with hepatitis B virus infection.

Renal involvement	Features
Chronic hepatitis B in absence of cirrhosis	Membranous nephropathy
	Membranoproliferative glomerulonephritis
	Mesangial proliferative glomerulonephritis
	Polyarteritis nodosa
	IgA nephropathy
	Amyloidosis
Use of antiviral drugs for hepatitis B	Reduction in GFR
	Proteinuria
	Proximal tubular damage
	Fanconi syndrome
	Osteomalacia
Cirrhosis due to hepatitis B	Acute kidney injury
	Hepatorenal syndrome
	Urinary tract infections

IgA: Immunoglobulin A; GFR: Glomerular filtration rate.

HBV-associated glomerulonephritis (HBV-GN) is the most common form of HBV-related kidney disease, followed by membranous nephropathy (MN). Other renal diseases include polyarteritis nodosa, immunoglobulin A nephropathy, and membranoproliferative glomerulonephritis. Polyarteritis nodosa may present with vasculitis-like symptoms such as fever, weight loss, and renal impairment; meanwhile, those with HBV-associated MN often develop proteinuria, which can lead to nephrotic syndrome. Mild or undiagnosed renal involvement may go untreated for an extended period before renal injury progresses to chronic kidney disease. HBV infection is an established risk factor for CKD[4].

PATHOGENESIS OF HBV-ASSOCIATED GLOMERULAR DISEASES

Multiple potential mechanisms, in absence of cirrhosis, are implicated in the pathogenesis of kidney injury in patients with HBV infection. Most renal manifestations, like other extrahepatic effects of HBV infection, are mediated by circulating immune complexes that activate serum complement, as evidenced by the deposition of hepatitis B antigen-antibody complexes in renal lesions observed via immunofluorescence microscopy[12]. Other potential mechanisms, involved in the pathogenesis of renal disease, include HBV-mediated cytopathic effects in renal cells, induction of a chronic inflammatory state in the kidney, or immune dysregulation. It remains unclear whether these mechanisms act alone or in combination to contribute to kidney injury in HBV-infected patients. The risk of developing renal injury in HBV infection may be determined by an array of factors such as HLA-mediated genetic susceptibility of the host[13], HBV viral load, HBV genotype, and cccDNA[14].

Immune complex deposition and glomerular injury

HBV-mediated glomerular diseases, seems to be largely mediated through immune complexes (ICs) formed by various HBV antigens [HBsAg, hepatitis B e antigen (HBeAg), and hepatitis B core antigen (HBcAg)], antibodies, complements, and other proteins (Figure 1). HBeAg is the most often involved antigen in HBV-GN[15]. These IC deposits vary in mechanism of their formation, deposition sites, composition, and quantity. Pre-formed ICs are trapped in the mesangium and the sub-endothelial surface of glomerular capillaries. Kidneys are susceptible to IC deposition because of high blood flow, relatively high blood pressure, large surface area, high permeability, and the negatively charged glomerular capillaries, which promote filling and deposition of ICs in the mesangium or capillary wall[12]. The deposition of ICs activates complement, damages podocytes, and causes proteinuria, which can lead to nephrotic syndrome, thickening of capillary walls, and mesangial proliferation[9,16].

Figure 1 Pathogenesis of hepatitis B induced, immune-mediated renal injury. HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core antigen.

Direct viral cytopathic effects

HBV can also cause tubulointerstitial nephritis and renal fibrosis by directly damaging renal tubular and glomerular cells. The viral-mediated mechanism of kidney injury is indicated by the presence of HBV DNA and HBV antigens in renal tubular cells, endothelial cells, and glomerular epithelial cells. Experimental studies have shown this effect through HBV DNA expression in glomeruli. Additionally, purified HBV has been shown to increase the proliferation of human mesangial cells and to induce the expression of type IV collagen and fibronectin[17]. However, the exact mechanism of this direct cytopathic effect remains unknown.

Chronic inflammation and immune dysregulation

HBV mediated chronic systemic inflammation activates cytokines [tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interferon-γ] and damages the kidneys. Persistent immunological activation leads to progressive kidney failure, tubulointerstitial fibrosis, and glomerular sclerosis.

HBV SEROPREVALENCE IN PEOPLE WITH CKD

HBV prevalence is determined by the seroprevalence of HBV infection markers. HBsAg indicates an active HBV infection; presence of either antibody against HBsAg (anti-HBs) or IgG anti-HBc in an unvaccinated person signifies naturally resolved past infection. Testing for HBsAg, IgG anti-HBc, HBV DNA, and anti-HBs help to estimate HBV prevalence in community. Several factors contribute to high HBV seroprevalence in CKD patients. Repeated exposure to contaminated blood and healthcare devices during dialysis, combined with an impaired immune response, increases their risk to acquire HBV infection. Uremia in CKD patients, especially those on MHD, impairs the performance of both humoral and cellular immunity. This immune impairment increases with the increasing severity of CKD.

HBsAg seroprevalence in CKD

CKD patients have higher HBV seroprevalence than the general community. A recent systematic review of global data, which summarized information from 795623 MHD individuals from 322 datasets, showed a pooled HBsAg seroprevalence of 7.57% worldwide; furthermore, the seroprevalence in Asia was estimated as 7.44%[18]. HBsAg seroprevalence ranged from 4.32% in North America to 9.73% in South America[18]. The seroprevalence globally was found to be many times higher than the estimates for individual countries or regions[1]. Currently, data are lacking on HBsAg seroprevalence among CKD patients who are not on MHD.

Occult HBV seroprevalence in CKD

Presence of HBV DNA, IgG anti-HBc, or anti-HBs antibody in blood of a HBsAg negative person—either alone or in combination—is used as a marker of occult HBV infection[19]. Recently, results from the National Health and Nutrition Examination Survey 2017-2020, showed that the seroprevalence of isolated core antibody was 7.9% in CKD patients compared to 5.2% in those with normal renal function; additionally, estimated glomerular filtration rate (eGFR) was significantly lower in the isolated anti-HBc positive group. The prevalence of CKD was also higher in individuals with isolated anti-HBc compared to those without core antibody. Moreover, when CKD patients were divided into stages 1 to 5, those with isolated anti-HBc showed a significantly higher frequency of advanced CKD stages than those in the non-HBV group[20]. In an excellent review, Fontenele et al[21] also summarized the reported seroprevalence of occult HBV in dialysis populations. Data from several studies reporting the seroprevalence of IgG anti-HBc in the MHD population are summarized in Table 2[22-30]. More data are needed to compare the seroprevalence of occult HBV between individuals with or without CKD, as well as across different CKD stages.

Table 2 Seroprevalence of markers of occult hepatitis B infection in people on maintenance hemodialysis as reported in a few of the major studies (%).

Ref.	Country	Number of participants	Proportion with seropositive status in unvaccinated HBsAg negative population
			HBV DNA	IgG anti-HBc	Anti-HBs	IgG anti-HBc + anti-HBs
Siagris et al[22], 2006	Greece	49	20.4	-	-	-
Yakaryilmaz et al[23], 2006	Turkey	188	2.7	6.4	-	-
Aghakhani et al[24], 2010	Iran	289	50% of IgG anti-HBc reactive	6.2	-	-
Mina et al[25], 2010	Greece	346	0.9	-	-	-
Helaly et al[26], 2015	Egypt	100	45.8% of IgG anti-HBc positive group	48	-	-
Sowole et al[27], 2015	United Kingdom	778	-	3	-	17
Kalantari et al[28], 2016	Iran	400	-	2.5	-	5.5
Tang et al[29], 2020	China	330	-	10.8	-	48
Farshadpour et al[30], 2023	Iran	274	11.7	24.1	-	-

HBV: Hepatitis B virus; DNA: Deoxyribonucleic acid; IgG: Immunoglobulin G; Anti-HBc: Anti hepatitis B core antibody; Anti-HBs: Hepatitis B surface antibody.

IMMUNE RESPONSE IN CKD

CKD, especially end-stage renal disease (ESRD), is a state of uremia that increases the risk of viral infections, impaired vaccine responses, and virus-related cancers. Uremia severely affects every cell involved in both adaptive and innate immunity[31]. The functions of T-cells and B-cells are compromised in adaptive immunity. Reduced activation of CD4+ and CD8+ T-cells leads to inadequate immune surveillance and weaker responses to vaccines and infections in dialysis patients[32], particularly due to decreased T-cell activity, which hampers virus clearance, unlike in individuals with a healthy immune system. This situation makes it more likely for an infection to become chronic, such as HBV. The immune response shows decreased T-cell proliferation, reduced cytokine production, and limited antibody formation[33]. The risk of HBV persistence and chronic infection grows with ongoing inflammation. The buildup of uremic toxins, oxidative stress, and endotoxemia results in a persistent low-grade inflammation known as the “inflammatory uremic milieu”, characterized by high levels of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β that further impair immune function. Consequently, liver conditions such as cirrhosis and hepatocellular carcinoma are more common in CKD patients. Regular HBV screening, better immunization programs, and strict infection control measures in dialysis units are crucial for reducing these risks.

NATURAL HISTORY OF ACUTE HBV INFECTION IN PEOPLE WITH CKD

Innate and acquired immune response in CKD patients are relatively impaired[31]. Data are limited on natural history of HBV infection in the MHD population because acute HBV infection goes unnoticed in majority because it remain asymptomatic and their serum liver enzyme levels are usually low[34]. Acute HBV infection in dialysis-dependent CKD patients follows a distinct clinical course as compared to healthy population. CKD patients typically develop only mild elevations of transaminase levels, remain anicteric, lack severe symptoms of acute hepatitis, experience prolonged viremia, delayed clearance of surface antigen, delayed or absent seroconversion to anti-HBs antibody, and face an increased risk of chronic infection[2].

Early identification of HBV infection, institution of strict infection control measures, and optimal antiviral treatment are crucial for preventing progression and transmission HBV in dialysis units. Patients with CKD are more susceptible to the consequences of HBV infection such as liver fibrosis and hepatocellular carcinoma (HCC). Infections in CKD patients, especially those on long-term dialysis, usually progress slowly and are characterized by low-grade inflammation and fluctuating alanine aminotransferase (ALT) levels. Cirrhosis is rare among dialysis patients, but the death rate for those with cirrhosis is 35% higher than for those without. This may be because the time needed for HBV-related complications like liver cirrhosis and HCC to develop likely exceeds the average life expectancy of many dialysis dependent patients. High mortality could also be linked to the difficulties which a HBV-reactive MHD patient faces in securing regular and timely dialysis sessions.

TREATMENT OF HEPATITIS B INFECTION

Evaluating the severity of liver disease in CKD

All the HBV infected people need evaluation to assess their liver disease severity with biochemical tests and virological markers, before starting treatment with antiviral drugs. In addition to hemogram and serum liver enzyme levels, patients are tested for HBeAg, anti-HBe antibody, and quantitative HBV DNA. The severity of liver disease is assessed to estimate liver fibrosis and parenchymal inflammation, which determine the indication for antiviral drugs, the choice of antivirals, and long-term prognosis. Though liver biopsy is the gold standard to assess liver fibrosis, it is an invasive test associated with a finite risk of complications and procedure related death. The risk of bleeding during liver biopsy is higher in those on MHD compared to those with normal renal function. Liver biopsy in HBV infected CKD patients is indicated only if noninvasive tests are discordant in terms of disease severity or if co-existence of dual pathology is suspected. Currently, various noninvasive methods, such as AST-Platelet Ratio Index (APRI), FIB-4, and transient elastography, are recommended to estimate liver fibrosis in CKD patients[10]. These non-invasive tests of fibrosis are reliable and well validated in patients with HBV infection and normal renal function. However, their use in patients on MHD may have serious limitations (Table 3). Overall, the performance of all noninvasive methods for assessing liver fibrosis appears suboptimal in the dialysis population; therefore, their results must be interpreted with caution. Transient elastography is one of the most widely used methods to assess liver fibrosis, but it may overestimate fibrosis in the MHD population due to fluid overload. A prospective study has shown that liver stiffness measured before renal transplantation, decreases markedly after normalization of renal function after successful transplantation[35].

Table 3 Non-invasive methods used to assess liver fibrosis and their potential limitations in patients with chronic kidney disease.

Method for liver disease severity	Interpretation about liver disease	Limitation(s) in patients with CKD
Pedal edema and/or ascites	It is a feature of decompensation and its presence indicate liver cirrhosis with significant portal hypertension	Pedal edema may be present due to fluid overload and hypoalbuminemia which is common in CKD patients
Low serum albumin level	Indicates poor synthetic function of the liver	Serum albumin may be low due to albuminuria or poor nutritional status
Liver biopsy	Gold standard for assessing liver fibrosis	High risk of bleeding in patients with CKD
APRI which require serum AST and Platelet counts	A widely-validated index whose value correlates well with significant liver fibrosis, and values > 2.0 strongly suggest the presence of cirrhosis	May underestimates liver fibrosis, because serum AST elevation is commonly attenuated in those with renal failure, particularly those on MHD
FIB-4 which is based on age, ALT, AST, and Platelet counts	A widely-validated index whose value correlates well with significant liver fibrosis, and values > 3.25 strongly suggest the presence of cirrhosis	May underestimates liver fibrosis, because serum elevation of ALT as well as AST is attenuated in those with renal failure, particularly those on MHD
Transient elastography	Measures liver stiffness, which correlates well with the stage of liver fibrosis, particularly in patients with HCV infection	Fluid overload adds to liver stiffness, leading to overestimation of the stage of liver fibrosis

APRI: Aspartate aminotransferase to platelet ratio index; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; FIB-4: Fibrosis-4 index; MHD: Maintenance hemodialysis; CKD: Chronic kidney disease.

Management of chronic HBV in the MHD population

HBsAg-positive CKD patients should be treated with nucleos(t)ide analogues (NAs) if they have HBV DNA levels greater than 2000 IU/mL, significant fibrosis on noninvasive tests, or moderate inflammation and/or significant fibrosis on histology, regardless of ALT levels. Entecavir (ETV) is the preferred NA for those with CKD, and can clear HBV DNA in up to 100% of naive patients at 24 months without causing significant toxicity. Tenofovir disoproxil fumarate (TDF) is not favored in patients with CKD because of its potential nephrotoxicity[36-39]. Tenofovir alafenamide (TAF), a newer analogue of TDF, is a promising alternative with a better renal safety profile[40]. Studies have shown that TAF is noninferior to TDF for DNA clearance and results in a milder reduction in creatinine clearance at weeks 48 and 96[41]. TAF use is not approved for the CKD patients on MHD; however, it remains a promising alternative.

Doses of all the NAs need adjustment based on eGFR values in patients with eGFR < 50 mL/minute, except for TAF, which does not require dose adjustment if eGFR is > 15 mL/minute. For eGFR 30-49 mL/minute: 300 mg of TDF 300 mg or ETV 0.5 mg should be administered every 48 hours. For eGFR 10-29 mL/min, TDF 300 mg or ETV 0.5 mg should be given every 72-96 hours. For subjects receiving MHD, TDF 300 mg or ETV 0.5 mg administered every 7 days after a hemodialysis session is recommended (Table 4)[10].

Table 4 Dose modifications of antiviral drugs recommended according to estimated glomerular filtration rate.

Antiviral drug	Creatinine clearance (mL per minute)
	> 50	30-49	10-29	< 10 or dialysis
Tenofovir disoproxil fumarate	300 mg tablet once a day	300 mg tablet every 48 hours	300 mg tablet every 72-96 hours	300 mg tablet every seven days or following completion of dialysis
Entecavir	0.5 mg tablet daily	0.5 mg tablet every 48 hours	0.5 mg tablet every 72 hours	0.5 mg tablet every week
Tenofovir alafenamide	25 mg tablet once a day	25 mg tablet once a day	25 mg tablet once a day up to creatinine clearance of 15 mL/minute	25 mg tablet after completion of dialysis

GFR: Glomerular filtration rate.

HBV management in renal transplant recipients

HBsAg-positive CKD patients who are started on NA should begin antiviral prophylaxis with NAs ≥ 2 weeks before renal transplantation. ETV is the preferred option due to its renal safety. After renal transplantation and normalization of renal function, the daily dose of NA must be adjusted according to the eGFR and continued for life. Although data are limited, ETV may be considered for switching to either TAF or TDF[42] after renal function normalizes[43]. Five-year follow-up data suggest that ETV and TAF are safe and effective in renal transplant recipients[44].

TENOFOVIR-ASSOCIATED NEPHROTOXICITY

Tenofovir metabolism

Tenofovir is the newest antiviral drug against HBV. It is a nucleotide analogue that inhibits the HBV reverse transcriptase. It has poor bioavailability on oral administration, hence used as prodrugs, either TDF or TAF, to improve absorption following oral administration. After absorption, TDF is quickly converted to tenofovir in circulation and is taken up by various tissues, including hepatocytes. Inside hepatocytes, tenofovir is metabolized into its active form, tenofovir diphosphate, which acts as a competitive inhibitor of HBV reverse transcriptase and terminates HBV DNA synthesis[36]. Conversely, after absorption, TAF is not converted into tenofovir but circulates as TAF, which is selectively taken up by hepatocytes. This selective distribution accounts for the much lower dose of TAF needed to produce similar clinical antiviral effects as the standard 300 mg dose of TDF[40]. Tenofovir is mainly excreted from the renal system in an unchanged form through a combination of glomerular filtration and active tubular secretion in proximal renal tubules[36].

Mechanism of nephrotoxicity

In proximal renal tubular cells, mitochondrial damage is the primary cause of TDF-induced nephrotoxicity[45]. Tenofovir causes oxidative stress, cell death, and mitochondrial dysfunction by inhibiting DNA polymerase γ, the only enzyme responsible for replicating mtDNA. Consequently, mitochondrial activity declines due to the depletion of mtDNA and several enzymes encoded by mtDNA that are involved in oxidative phosphorylation and the electron transport chain. Tenofovir functions as a mitochondrial toxin in renal tubular cells[37,46]. Additionally, lysosomal dysfunction caused by increased intracellular tenofovir levels directly damages the tubules. Tenofovir is expelled by multidrug resistance-associated protein 4 (MRP4) after entering proximal tubule cells via organic anion transporters (OAT1 and OAT3)[38]. Dysfunction of MRP4 leads to the buildup of tenofovir inside cells and heightened toxicity, which can result in proximal tubulopathy, presenting as Fanconi syndrome characterized by bicarbonate wasting, phosphaturia, glycosuria, and aminoaciduria. Chronic exposure further impairs renal function and promotes tubulointerstitial fibrosis through inflammatory cytokines like TGF-β and IL-6.

Clinical manifestations of tenofovir nephrotoxicity

Tenofovir nephrotoxicity causes multiple renal abnormalities, primarily affecting the proximal tubules. Among the clinical signs are acute kidney injury, which is defined by a sharp rise in blood creatinine and a decrease in the eGFR. Patients may experience metabolic acidosis, electrolyte abnormalities, and oliguria. Chronic exposure can lead to interstitial fibrosis, proteinuria, and a progressive loss of renal function, all of which are signs of CKD[39]. Although it is often asymptomatic at first, as CKD worsens, it can lead to fatigue, hypertension, and fluid retention. A characteristic of tenofovir toxicity is Fanconi syndrome, resulting from proximal tubular dysfunction[47]. Symptoms of this disorder include bicarbonate wasting, hypophosphatemia, glucosuria (with normal blood glucose levels), and aminoaciduria, which causes metabolic acidosis. Due to phosphate depletion, patients may experience bone pain, muscle weakness, and an increased risk of osteomalacia. Continuous tenofovir use is also associated with electrolyte imbalances, including hypokalemia and hypomagnesemia, which can lead to arrhythmias, muscle cramps, and neuromuscular symptoms. In severe cases, patients may experience excessive thirst and polyuria due to nephrogenic diabetes insipidus. For early detection and prevention of irreversible kidney injury, routine renal function monitoring is crucial.

Risk factors for tenofovir nephrotoxicity in CKD patients

The risk of tenofovir-induced renal injury increases with age and certain co-morbidities such as diabetes and hypertension[47]. Additionally, using nephrotoxic drugs such as calcineurin inhibitors, aminoglycosides, non-steroidal anti-inflammatory drugs, and contrast agents can impair kidney function and intensify tenofovir’s toxic effects. Underweight individuals have higher plasma tenofovir levels, which increases tubular exposure and the risk of toxicity. Low body weight and malnutrition contribute to this risk. Long-term tenofovir use can cause cumulative kidney damage, including chronic kidney disease and progressive tubulointerstitial fibrosis.

Furthermore, because ongoing immune activation and viral-related nephropathy further harm kidney function, CKD patients with HIV or HBV infections are especially vulnerable. Genetic factors may affect an individual’s risk of tenofovir toxicity, including polymorphisms in renal transporters like ABCC2 and ABCC4[48]. Regular kidney function monitoring, dose adjustments based on eGFR, and switching to TAF in high-risk patients are crucial strategies to reduce these risks.

HEPATITIS B PREVENTION IN PATIENTS WITH CKD

Patients with CKD, especially those receiving hemodialysis, are at high risk of contracting HBV infection due to their impaired immune systems and increased exposure to contaminated blood. This infection can accelerate the disease's progression, increasing morbidity and mortality. HBV vaccination is a key preventive measure to reduce the risk of infection and its consequences. According to the Kidney Disease Improving Global Outcomes guideline, all patients with G4 and G5 CKD, whose eGFR is less than 30 mL/minute/1.73 m², should be advised about and considered for kidney transplantation. Early HBV vaccination, before eGFR drops below 15 mL/minute/1.73 m², is recommended for CKD patients likely to need kidney replacement therapy to improve their immune response[49]. Vaccination against HBV is advised for all CKD patients who are anti-HBs negative, especially those on dialysis and awaiting kidney transplants. The most common hepatitis B vaccine is a subunit vaccine containing HBsAg. The three generations of hepatitis B vaccines are shown in Table 5. The standard hepatitis B vaccination schedule involves three intramuscular doses at 0, 1, and 6 months, each containing 20 μg. This vaccination triggers both humoral and cell-mediated immune responses, with T-cells supporting long-term immunity and B-cells producing anti-HBs antibodies. The standard protocol provides seroprotection (anti-HBs titer ≥ 10 mIU/mL) to over 95% of healthy adults but may not confer protection to immunocompromised individuals or those on MHD[50].

Table 5 Three generations of hepatitis B vaccines.

Vaccine generation	Hepatitis B antigen	Examples	Remarks
First	SHBs protein	Heptavax-B (Merck & Co., United States); Hevac B (Pasteur, France); KGC (Korea Green Cross, Korea)	Not in use
Second	SHBs, MHBs protein	Recombivax (Merck & Co., United States); Engerix-B (GSK, Belgium); TGP 943 [P31] (Takeda, Japan); Fendrix (GSK, Belgium); HBVaxPro (Sanofi-Pasteur, MSD)	Most commonly used and easily available
Third	SHBs, MHBs, Large hepatitis B surface protein	GenHevac B (Pasteur, France); Bio-Hep-B (Bio Technology General, Israel)	Limited availability and higher costs

SHBs: Small hepatitis B surface; MHBs: Medium hepatitis B surface.

Hepatitis B vaccination for individuals on MHD

Several uncontrolled studies have reported seroprotection rates between 50% and 60% in ESRD patients[51]. This reduced efficacy results from numerous factors, including uremia, decreased antigen presentation, impaired T-cell activation, and ongoing inflammation. Given the diminished immune response in this group, all CKD patients, including those with ESRD, receive four double doses (2.0 mL each, containing 40 μg of HBsAg instead of the usual 1.0 mL) of hepatitis B vaccine, administered at 0, 1, 2, and 6 months[52].

Booster doses and revaccination strategies

A booster dose is necessary for dialysis patients due to their weaker immune systems and rapid decline in antibody levels. A booster dose is needed when anti-HBs antibody levels fall below the 10 mIU/mL protective threshold. Five years after vaccination, only 40%-60% of CKD patients still maintain adequate antibody levels. Consequently, routine monitoring usually occurs once a year to help identify when a booster is needed[53]. Individuals with diabetes, hemodialysis patients, older adults with chronic kidney disease, and those with a lower initial immune response are particularly prone to early antibody decline; therefore, they are prioritized for booster shots. A complete revaccination series (four doses of 40 μg at 0 months, 1 months, 2 months, and 6 months) may be required if a patient's antibody levels remain low or undetectable even after booster doses. Additionally, some studies suggest that patients who do not respond well to standard intramuscular vaccines might benefit from intradermal vaccines[53,54].

Pre-transplant management of patients with CKD who are chronically HBV-positive

To prevent HBV reactivation, liver complications, and graft dysfunction, managing chronic HBV-positive patients with CKD after kidney transplantation requires a comprehensive approach. To assess the severity of the disease, the pre-transplant examination should include liver function tests, fibrosis assessment, and HBV DNA measurement. Prior to transplantation, antiviral treatment with nucleos(t)ide analogues [such as entecavir or tenofovir alafenamide (TAF)] is recommended to suppress viral replication and reduce the risk of post-transplant reactivation[55]. Furthermore, since immunosuppressive therapy after transplant diminishes vaccine effectiveness, HBV-negative CKD patients awaiting transplantation should receive hepatitis B immunization as soon as possible. Antiviral treatment must continue to maintain viral suppression throughout transplantation, and immunosuppressive regimens should be carefully selected to minimize the risk of HBV reactivation. Hepatitis B immune globulin may be administered to certain high-risk patients for added protection[56].

Hepatitis B prophylaxis for kidney recipients from an HBsAg-positive donor

There is a significant risk of HBV transmission when recipients, especially those who are HBV-naive or non-immune, receive kidney transplants from HBsAg-positive donors. Therefore, a clear prevention plan is necessary. Regarding donor-derived infection, small case reports indicate that HBV-immune patients can safely undergo renal transplantation from HBsAg-positive donors without evidence of HBV transmission, provided that recipients have anti-HBsAg titres (> 10 IU/mL)[57,58]. Therefore, HBV vaccination is recommended for HBV seronegative patients with end-stage renal disease. Additionally, in patients with resolved past infection (HBcAb-positive), vaccination should be considered to boost anti-HBsAg titres and reduce the risk of reactivation. Patients with anti-HBsAg titres below 10 IU/mL are given nucleos(t)ide analogue therapy for 6-12 months to prevent donor-to-recipient infection[59].

CONCLUSION

Patients with chronic kidney disease are vulnerable to hepatitis B infection. Routine vaccination is an effective way to reduce the spread of hepatitis B among these patients. With the availability of highly effective antivirals, patients with chronic kidney disease who contract hepatitis B can be treated successfully.