Kidney disease associated with hepatitis B virus infection

INTRODUCTION — Infection with hepatitis B virus (HBV) may be associated with a variety of kidney diseases [1-3]. The three most common types of kidney disease resulting from HBV infection are:

●Membranous nephropathy

●Membranoproliferative glomerulonephritis (MPGN)

●Polyarteritis nodosa (PAN)

In addition, HBV infection has been associated with mesangial proliferative glomerulonephritis, immunoglobulin A (IgA) nephropathy, crescentic glomerulonephritis, focal segmental glomerulosclerosis (FSGS), minimal change disease, and amyloidosis, although the causative role of HBV has been debated for some of these conditions.

This topic provides an overview of types of kidney disease associated with HBV infection, as well as the diagnosis and management of such patients. Additional discussions of HBV in patients receiving hemodialysis and in patients undergoing kidney transplantation are presented elsewhere:

●(See "Hepatitis B virus and dialysis patients".)

●(See "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients".)

EPIDEMIOLOGY — Kidney disease associated with HBV infection most commonly occurs in endemic areas. In these areas, infection is more likely to occur during infancy and early childhood, which increases the probability of becoming a chronic carrier [4]. By comparison, the frequency of HBV-related kidney disease is low in patients born in the United States and western Europe due to the lower prevalence of chronic HBV infection in general and a lower likelihood of childhood infection [4]:

●(See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Epidemiology of chronic HBV'.)

●(See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".)

The widespread use of hepatitis B vaccination has decreased the incidence of HBV-related membranous nephropathy and membranoproliferative glomerulonephritis (MPGN), providing evidence of the probable etiologic role of HBV [5,6]. (See "Hepatitis B virus immunization in adults".)

PATHOGENESIS — Patients with HBV-related kidney disease are positive for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) and, in those with membranous nephropathy, hepatitis B e antigen (HBeAg). Although some patients with HBV-related kidney disease have a history of active hepatitis, a large proportion of patients have only mild to moderate elevations in serum aminotransferases.

The pathogenetic role of HBV infection has been documented primarily by the demonstration of hepatitis B antigen-antibody complexes in the kidney lesions via immunofluorescence microscopy, including deposition of HBeAg in membranous nephropathy [1,7,8]. The relationship between HBV variants (eg, precore and core promoter mutations) that prevent or decrease HBeAg production (despite active viral replication by DNA testing) and kidney disease has not been well described. (See "Clinical significance and molecular characteristics of common hepatitis B virus variants", section on 'Precore and core promoter variants'.)

The pathogenesis of HBV-associated glomerular diseases has been attributed to the deposition of immune complexes, which trigger downstream inflammatory pathways. HBV DNA and HBV RNA have been localized to glomerular and tubular cells in affected patients; however, the role of these viral nucleic acids in the development of kidney injury remains to be confirmed [9,10]. There is evidence that the virus may directly trigger pathological processes in the kidney. As an example, purified HBV can induce human glomerular mesangial cell proliferation and expression of type IV collagen [11]. HBV X protein, which regulates HBV transcription and replication, can modulate signaling pathways and has been shown to induce a proinflammatory phenotype and stimulate epithelial-mesenchymal transition in kidney tubular epithelial cells [12-15]. Data from single-cell RNA sequencing of kidney biopsies showed increased gene activation related to extracellular matrix formation in podocytes and inflammatory pathway and apoptotic signaling pathway gene activation in endothelial cells [16].

TYPES OF KIDNEY DISEASE — The kidney diseases most commonly associated with HBV infection include membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), and polyarteritis nodosa (PAN) [1,2,7]. In addition, HBV infection has less commonly been associated with other kidney lesions such as mesangial proliferative glomerulonephritis [9,17], IgA nephropathy [18], focal segmental glomerulosclerosis (FSGS) [19], minimal change disease [20], and amyloidosis [21].

In addition to specific forms of glomerular diseases, HBV infection is associated with increased incidence and prevalence rates of chronic kidney disease (CKD) in endemic regions such as Taiwan, China, and South Korea [22-24]. Analysis of nationwide health insurance data showed that antiviral treatment with nucleoside/nucleotide analogs was associated with a reduced risk of developing end-stage kidney disease in patients with CKD and HBV infection, with 16-year cumulative rates of 10.1 percent and 2.2 percent in the untreated and antiviral-treated populations, respectively [25].

The discussion below focuses on the relationship of HBV to the most commonly associated kidney conditions. The clinical manifestations of these three diseases are discussed in detail elsewhere:

●(See "Membranous nephropathy: Pathogenesis and etiology".)

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

●(See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

Membranous nephropathy — HBV-associated secondary membranous nephropathy, as with other forms of membranous nephropathy, usually presents with proteinuria, which can be in the nephrotic range. Compared with patients who have idiopathic or primary membranous nephropathy, patients with HBV-associated membranous nephropathy are more likely to have microscopic hematuria and lower complement levels [26]. The histologic presence of mesangial cell proliferation or mesangial or subendothelial immune deposits, in addition to the typical subepithelial localization, may be a clue to suggest secondary rather than primary membranous nephropathy.

The phospholipase A2 receptor (PLA2R) has been implicated as the major antigen involved in the pathogenesis of primary membranous nephropathy (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'). Several studies have shown a low prevalence of anti-PLA2R antibodies and/or PLA2R staining of the immune deposits in HBV-associated membranous nephropathy. However, one retrospective study of 39 Chinese patients with hepatitis B-associated membranous nephropathy found that 64 percent of cases exhibited strong PLA2R staining of immune deposits [27]. Staining for the hepatitis B surface antigen (HBsAg) colocalized with PLA2R within the deposits. Among the six patients for whom serum was available, all were positive for anti-PLA2R antibodies. In another report that included 50 patients with HBV-associated membranous nephropathy (and 56 patients with primary membranous nephropathy), four patients (8 percent) tested positive for anti-PLA2R antibodies in serum and five patients (10 percent) were positive for PLA2R in the kidney tissue [28]. The association between hepatitis B infection and PLA2R-positive membranous nephropathy needs to be validated by further studies.

It has been proposed that the deposition of hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) immune complexes in the subepithelial region of the glomerular basement membrane is pivotal to disease pathogenesis [1,7,8,29]. HBV-associated membranous nephropathy is more common in children and resolves spontaneously in many cases, usually in association with seroconversion from HBeAg to anti-HBe [7]. By contrast, spontaneous resolution is relatively uncommon in adults, and some patients show progressive kidney deterioration over time [2,8,30]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Etiology'.)

Membranoproliferative glomerulonephritis (MPGN) — HBV-associated MPGN, as with other forms of MPGN, presents with hematuria (often with dysmorphic red blood cells and/or red blood cell casts), variable degrees of proteinuria, reduced glomerular filtration rate (GFR), and hypertension. The deposition of circulating antigen-antibody complexes in the mesangium and subendothelial space characterizes the MPGN associated with HBV. Both HBsAg and HBeAg deposition have been implicated in this disorder, although their exact role remains uncertain [7]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Infections'.)

Compared with hepatitis C infection, HBV infection is a rare cause of mixed cryoglobulinemia, which can be associated with MPGN [31-33]. In one series of 12 patients with HBV-associated cryoglobulinemia, all patients had nephrotic-range proteinuria and microscopic hematuria, and nine (75 percent) had impaired kidney function [33]. A purpuric rash was present in more than one-half of the patients (58 percent), and all patients had evidence of hypocomplementemia and were positive for rheumatoid factor. Histologic features of MPGN were present in the kidney biopsies of all patients; only three patients had glomerular deposits of HBsAg, hepatitis B core antigen (HBcAg), or HBeAg. One-half of the patients died or developed end-stage kidney disease during follow-up despite having received various immunosuppressive and antiviral treatments. (See "Overview of kidney disease associated with hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Polyarteritis nodosa (PAN) — PAN is a necrotizing vasculitis affecting small- and medium-sized blood vessels that frequently involves multiple organs; kidney involvement leads to variable degrees of reduced GFR and hypertension. The clinical features of HBV-associated PAN are similar to idiopathic PAN. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

HBV-associated PAN typically occurs within four months after the onset of HBV infection [34]. The presence of HBV-associated disease is suggested by the findings of HBsAg, HBeAg, and HBV DNA (an indicator of viral replication) in the serum. The deposition of circulating antigen-antibody immune complexes in the vessel wall triggers downstream inflammatory processes [1,2]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Pathogenesis'.)

DIAGNOSIS — The diagnosis of HBV-associated kidney disease should be suspected in patients with acute or chronic HBV infection who present with clinical and/or laboratory features suggestive of glomerular disease (eg, proteinuria and/or hematuria, acute kidney injury [AKI] or deterioration in kidney function, with or without hypertension and/or edema). It is particularly important to consider this diagnosis in patients from endemic areas, where both acute and chronic HBV infection are more prevalent. A kidney biopsy is often required to confirm the presence of an underlying glomerular process, although a different tissue site may be biopsied to confirm polyarteritis nodosa (PAN). (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Biopsy' and "Glomerular disease: Evaluation and differential diagnosis in adults".)

In addition, a diagnosis of HBV-associated kidney disease should be considered in all patients with unknown HBV status who have evidence of nephrotic syndrome or glomerulonephritis or are found on kidney biopsy to have histologic evidence of membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), or PAN. Such patients should be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) as part of their initial evaluation. If either is positive, additional testing for hepatitis B surface antibody (anti-HBs), hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe), and HBV DNA should be performed as appropriate to ascertain the viral replicative state. Concurrent infection with hepatitis C virus (HCV) or HIV should be considered and investigated as appropriate. (See "Hepatitis B virus: Screening and diagnosis in adults" and "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection' and "Screening and diagnosis of chronic hepatitis C virus infection" and "Screening and diagnostic testing for HIV infection".)

A presumptive diagnosis of HBV-associated kidney disease can be made in patients who are HBsAg positive and have biopsy-proven membranous nephropathy, MPGN, or PAN [1,2], particularly if the patient is a child from an endemic area or an adult without another identifiable cause for the kidney disease. Such patients are often HBeAg positive. However, confirming the etiologic role of HBV in any of these disorders may, at times, be difficult, since the detection of viral antigen deposition in the kidney requires techniques that may not be available in many clinical settings. In addition, the presence of viral antigens in the kidney tissue may be coincidental rather than indicative of a causal relationship [7]. Proof that HBV is the primary cause of the kidney disease can only be provided by improvement in the kidney disease with antiviral therapy and viral suppression.

Diagnosing HBV-associated kidney disease is important because therapy with glucocorticoids, cytotoxic, or immunomodulatory agents, which are common therapies for primary forms of the above disorders, may not be beneficial in patients with HBV-associated kidney disease and may lead to reactivation of HBV replication, hepatitis flares, and liver failure if used without antiviral therapy.

TREATMENT — The treatment of HBV-associated kidney diseases consists of antiviral therapy in most patients. This recommendation is consistent with treatment guidelines produced by Kidney Disease: Improving Global Outcomes (KDIGO) [35]. By contrast, immunosuppressive therapy, with or without plasmapheresis, is used only in select patients (eg, rapidly progressive glomerulonephritis [RPGN] or polyarteritis nodosa [PAN] with severe manifestations), and when it is administered, it should always be used in combination with antiviral therapy.

The limited data on the treatment of HBV-associated kidney diseases are based upon small case series and clinical trials. In addition, antiviral therapy in children and adults with HBV-associated kidney disease differs because the natural history of such diseases also differs.

Antiviral therapy

Indications for antiviral therapy — We recommend antiviral therapy for patients with HBV-associated kidney disease and detectable serum HBV DNA or positive hepatitis B e antigen (HBeAg). This recommendation is based primarily upon data from observational studies and uncontrolled trials that suggest antiviral therapy is associated with reduced proteinuria [2,8,17,30,36-48].

The following examples illustrate the quality of the data:

●A retrospective report from the National Institutes of Health (NIH) evaluated 15 adults (10 with membranous nephropathy, four with membranoproliferative glomerulonephritis [MPGN], and one in whom kidney biopsy was not available) who were treated with 5 million units of interferon alfa-2b subcutaneously daily for 16 weeks [38]. Eight responded with seroconversion of HBeAg to hepatitis B e antibodies (anti-HBe) and a reduction of HBV DNA to undetectable levels by hybridization assay. In seven patients, this was accompanied by gradual disappearance of proteinuria. Responders had lower baseline HBeAg and HBV DNA levels than nonresponders. In responders, remission persisted for a long period after therapy was discontinued. Patients with membranoproliferative disease appeared less responsive to treatment. The dose of interferon alfa-2b was lowered in seven patients due to side effects (fatigue or anemia). In two patients, therapy was discontinued (one patient had intractable fatigue, and the other had a seizure).

Other studies that examined interferon alfa for HBV-associated kidney disease reported sustained seroconversion of HBeAg to anti-HBe in 38 to 80 percent of patients and remission of proteinuria in 25 to 100 percent of patients [17,30,39,40]. Interferon alfa-2b was discontinued by its manufacturer in 2019.

●Ten adult patients with HBV-associated membranous nephropathy were treated with the nucleoside analog lamivudine and were compared with 12 historical controls who had the same diagnosis but were not treated with lamivudine [46]. Treatment with lamivudine was associated with disappearance of HBV DNA and reduction of proteinuria. Six of 10 treated and 3 of 12 untreated patients had remission of proteinuria to <0.3 g/24 hours. Preliminary data in patients treated with entecavir or adefovir also showed a benefit in kidney outcome [47]. There are anecdotal data on the efficacy of lamivudine in HBV-associated MPGN [41].

●A meta-analysis of 10 studies (including four randomized, controlled trials) involving 325 patients evaluated the efficacy of nucleoside/nucleotide monotherapy in patients with HBV-associated glomerulonephritis [48]. Of the 10 studies, five evaluated entecavir, four evaluated lamivudine, and one evaluated adefovir. Treatment with nucleoside/nucleotide monotherapy was associated with higher rates of proteinuria remission to <0.3 g/24 hours, disappearance of HBV DNA, and clearance of HBeAg. All the patients included in the meta-analysis were from Asia, and therefore, the generalizability of these results to other patient populations or nonendemic areas is unclear.

Choice of therapy — Both interferon alfa and nucleoside/nucleotide analogs have been used to treat patients with HBV-associated kidney disease. In general, we prefer pegylated interferon (PegIFN) alfa-2a in children and young adults since clinical studies in these populations have shown efficacy in inducing remission of HBV-related glomerulonephritis [49]. However, we generally avoid the use of interferon in patients who present with RPGN. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogs' and "Management of hepatitis B virus infection in children and adolescents" and 'Rapidly progressive glomerulonephritis (RPGN)' below.)

Interferon is less well tolerated but is more likely to induce a sustained remission. Thus, it should be considered in children and young adults who can better tolerate interferon or who do not want to be on prolonged nucleoside/nucleotide therapy. We prefer PegIFN, which has superseded standard interferon in the treatment of chronic hepatitis B, although it has not been studied in patients with HBV-associated kidney disease. The dose of PegIFN should be adjusted according to kidney function (PegIFN alfa-2a should be dosed as 135 mcg/week if the estimated glomerular filtration rate [eGFR] is <30 mL/min/1.73 m²). Additional information on the use of interferon for the treatment of chronic HBV is presented elsewhere. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

We prefer nucleoside/nucleotide analogs rather than interferon in older adults and patients who are not candidates for interferon therapy, regardless of age. As an example, interferon should be avoided in patients with cirrhosis (table 1). (See "Hepatitis B virus: Overview of management", section on 'Antiviral therapy' and "Pegylated interferon for treatment of chronic hepatitis B virus infection" and "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients".)

When a nucleoside/nucleotide analog is used, entecavir or tenofovir is preferred in view of their antiviral efficacy, low propensity for drug resistance, and safety profiles. The dose of nucleoside/nucleotide analog often needs to be reduced in patients with impaired kidney function (table 2). If tenofovir is used, we generally prefer tenofovir alafenamide to tenofovir disoproxil fumarate because it is associated with a lower risk of kidney toxicity and can be used in patients with impaired kidney function with an eGFR >15 mL/min/1.73 m² [50,51]. By contrast, we try to avoid tenofovir disoproxil fumarate in patients with reduced kidney function, given the potential risk of additional kidney injury. Adefovir, lamivudine, and telbivudine are not preferred due to a high rate of resistance after the first year and/or weak antiviral activity. (See "Hepatitis B virus: Overview of management", section on 'Antiviral therapy'.)

If initial therapy with interferon is ineffective or not well tolerated, we will switch to a nucleoside/nucleotide analog. Conversely, if initial therapy with a nucleoside/nucleotide analog fails, we will consider a course of interferon.

Duration of therapy — Patients receiving interferon therapy receive a finite duration of therapy. The optimal duration of therapy for the oral drugs is not well established. Most patients receiving nucleoside/nucleotide analog therapy will require at least four to five years of treatment, and many require an indefinite duration of treatment (table 1). The administration of immunosuppressive therapy, if indicated, may also impact the duration of therapy (see 'Immunosuppression and plasmapheresis in select patients' below). More detailed discussions of the duration of antiviral therapy for patients with chronic HBV are presented elsewhere:

●(See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

●(See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Immunosuppression and plasmapheresis in select patients — For most patients with HBV-associated kidney disease, treatment with antiviral therapy alone is sufficient. However, immunosuppression, with or without plasmapheresis, in combination with antiviral therapy may be beneficial in patients who have:

●RPGN

●PAN with severe manifestations

Except for these two indications, data from most observational studies suggest that immunosuppressive therapy with glucocorticoids or cytotoxic agents and plasmapheresis are of little benefit and are potentially harmful. This is particularly true among children with membranous nephropathy in whom spontaneous recovery over 6 to 24 months is common [1,2,29]. Antiviral monotherapy may also be sufficient to treat HBV-associated PAN in patients who do not have severe or life-threatening disease [42-44]. In addition, immunosuppressive therapy can trigger an increase in viral replication and possibly lead to exacerbation of chronic hepatitis [52-54].

There may be a potential role for immunosuppressive agents in the treatment of refractory cases of HBV-associated membranous nephropathy. In one report of two adult patients with HBV-associated membranous nephropathy, positive phospholipase A2 receptor (PLA2R) staining on kidney biopsy, anti-PLA2R seropositivity, and persistent proteinuria despite effective suppression of HBV DNA with entecavir, the addition of rituximab led to remission of proteinuria and disappearance of anti-PLA2R [55]. The authors postulated that HBV was the trigger of autoimmunity leading to anti-PLA2R-mediated membranous nephropathy. Another report described the clinical course of a patient with MPGN whose proteinuria did not improve despite seven months of entecavir treatment but responded to the addition of prednisolone [56]. The generalizability of this sequential therapeutic approach remains to be established.

Immunosuppressive treatment must always be accompanied by antiviral therapy since it may lead to increased viral replication and a flare of hepatitis [57]. The type of immunosuppressive treatment may also impact the duration of antiviral therapy.

Rapidly progressive glomerulonephritis (RPGN) — In rare patients with RPGN with extensive crescentic disease, presumed to be due to HBV infection, we suggest both antiviral medication (preferably a nucleoside/nucleotide analog) and a short course of high-dose glucocorticoids with or without an immunosuppressant, such as cyclophosphamide or rituximab. The glucocorticoid regimen consists of intravenous methylprednisolone, 500 to 1000 mg/day for up to three days, followed by prednisone, 0.7 to 1 mg/kg per day, tapered over four to six months. We generally avoid the use of interferon in these patients, given the lack of data on efficacy and the theoretical possibility that interferon could stimulate the immune response involved in crescent formation. (See "Mechanisms of glomerular crescent formation".)

Antiviral therapy and monitoring of HBV DNA levels are continued for at least six months after cessation of immunosuppressive therapy (or at least 12 months if an anti-CD20 antibody is used) or until the therapeutic goal for hepatitis B is achieved. (See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

The treatment of RPGN associated with mixed cryoglobulinemia and HBV infection is discussed separately. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Hepatitis B infection'.)

Polyarteritis nodosa (PAN) — In patients with mild PAN, we suggest antiviral therapy alone. However, in patients with PAN and severe manifestations (defined by the presence of ulcerative or gangrenous lesions of the extremities, acute kidney injury [AKI], polyneuropathy, central nervous system involvement, mesenteric arteritis, or myocardial ischemia), we suggest both glucocorticoids and plasmapheresis in addition to antiviral therapy (preferably a nucleoside/nucleotide analog). (See 'Choice of therapy' above.)

The glucocorticoid and plasmapheresis regimens that we use are as follows:

●Prednisone 0.7 to 1 mg/kg per day, tapered over four to six months

●Plasma exchange, 2.5 to 4 liters per session for a total of 6 to 10 sessions, daily or on alternate days, over two to three weeks

As with RPGN, antiviral therapy and monitoring of HBV DNA levels are continued for at least six months after cessation of immunosuppressive therapy or until the therapeutic goal for hepatitis B is achieved, whichever is longer. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

Although the data supporting the use of plasma exchange are weak, immunosuppression and plasma exchange are part of published treatment protocols for HBV-associated PAN [34,42-44,58-62]. Glucocorticoids suppress the inflammatory component of the vasculitis [29,34] and may improve survival [63], although they can enhance viral replication and lead to exacerbation of chronic hepatitis. Plasmapheresis removes circulating immune complexes, which may be beneficial in patients with severe disease manifestations.

The benefits of treating HBV-associated PAN with immunosuppression and plasmapheresis in combination with antiviral therapy were shown in a retrospective series of 80 patients with HBV-associated PAN who were treated with an antiviral agent (vidarabine, interferon alfa, or lamivudine, depending upon the era), a two-week course of glucocorticoids, and an intensive schedule of plasma exchange [64]. Their clinical course and outcomes were compared with 35 historic controls (before the antiviral era) treated with glucocorticoids with or without cyclophosphamide, with most receiving plasma exchange. The following observations were made:

●Remission was attained by 81 percent of all patients; patients who did not achieve remission died within a mean of 178 days. Overall five-year survival was 73 percent.

●At a median of 237 months, combination therapy with antivirals, immunosuppression, and plasmapheresis was associated with lower rates of relapse (4 versus 14 percent) and death (30 versus 49 percent), although the differences did not reach statistical significance.

●Combination therapy was associated with a significantly higher rate of HBeAg seroconversion to anti-HBe (49 versus 15 percent), which predicted a sustained remission. Seroconversion rates were similar for interferon and lamivudine (both over 60 percent) but lower for vidarabine (41 percent), which is no longer used due to neurotoxicity.

The addition of cyclophosphamide to glucocorticoids and plasma exchange does not appear to improve long-term outcomes in HBV-associated PAN, although it may contribute to more rapid control of disease [58,64]. There are no data on the role of other immunosuppressive agents, including mycophenolate mofetil and rituximab, in the treatment of HBV-associated PAN [65,66], although some clinicians may choose to use one of these agents to spare the use of glucocorticoids. Although there are case reports on the efficacy of tocilizumab or adalimumab in refractory or relapsing PAN, there are no data to support their use in HBV-associated PAN [67,68].

PATIENTS WITH CONCOMITANT HCV INFECTION — The management of patients with concomitant hepatitis C virus (HCV) infection is complex. The choice of therapy depends upon the state of viral replication of the two viruses. HBV DNA and HCV RNA levels should be measured to determine if patient has HCV viremia.

In patients with HBV and HCV coinfection (HCV RNA detected) and glomerulonephritis, initial therapy typically consists of the combination of direct-acting antivirals for treatment of HCV plus nucleoside/nucleotide analogs to treat HBV [69]. Although interferon may seem like the logical therapeutic choice since it is active against both viruses, treatment of HCV with direct-acting antivirals is better tolerated and associated with higher rates of sustained virologic response and remission of glomerulonephritis associated with HCV cryoglobulinemia. However, direct-acting antivirals for treatment of HCV may lead to reactivation of HBV in patients who are hepatitis B surface antigen (HBsAg) positive and in such patients should be used together with nucleoside/nucleotide analogs for treatment of HBV. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'HBV coinfection' and "Overview of kidney disease associated with hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Hepatitis B virus: Clinical manifestations and natural history", section on 'Coinfection with HCV or HDV'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Infection with hepatitis B virus (HBV) may be associated with a variety of kidney diseases. The three most common types of kidney disease resulting from HBV infection are membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), and polyarteritis nodosa (PAN). (See 'Introduction' above.)

●Diagnosis – The diagnosis of HBV-associated kidney disease should be considered in:

•Patients with acute or chronic HBV infection, particularly those from endemic areas, who present with clinical and/or laboratory features suggestive of glomerular disease (eg, proteinuria and/or hematuria, acute kidney injury [AKI] or deterioration in kidney function, with or without hypertension and/or edema). A kidney biopsy is often required to confirm the presence of an underlying glomerular process, although a different tissue site may be biopsied to confirm PAN.

•Patients with unknown HBV status who are found on kidney biopsy to have histologic evidence of membranous nephropathy, MPGN, or PAN. Such patients should be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). If positive, additional testing for hepatitis B e antigen (HBeAg) and HBV DNA should be performed.

A presumptive diagnosis of HBV-associated kidney disease can be made in patients with biopsy-proven membranous nephropathy, MPGN, or PAN whose serologic tests show circulating HBsAg, particularly if the patient is a child from an endemic area or an adult without another identifiable cause for the kidney disease. (See 'Diagnosis' above.)

●Treatment

•Antiviral therapy – For patients with presumed HBV-associated kidney disease and detectable serum HBV DNA or positive HbeAg, we recommend antiviral therapy (Grade 1B). (See 'Indications for antiviral therapy' above.)

-For most children and young adults, we suggest initial therapy with interferon alfa (usually pegylated interferon [PegIFN] alfa) rather than nucleoside/nucleotide analogs if there are no contraindications (Grade 2C). Interferon is less well tolerated but is more likely to induce a sustained remission.

-For older adults and in patients with contraindications to interferon alfa (eg, cirrhosis), we suggest initial therapy with nucleoside/nucleotide analogs rather than interferon (Grade 2C). Entecavir or tenofovir alafenamide is preferred. The dose of most nucleoside/nucleotide analogs needs to be reduced in patients with impaired kidney function (table 2).

-The duration of therapy depends upon the type of drug used and the patient's serologic response to therapy. (See 'Duration of therapy' above.)

•Immunosuppression and plasmapheresis in select patients – For most patients with HBV-associated kidney disease, treatment with antiviral therapy alone is sufficient. Immunosuppressive therapy with glucocorticoids or cytotoxic agents and plasmapheresis are of little benefit and are potentially harmful. However, immunosuppression (with or without plasmapheresis) in combination with antiviral therapy may be beneficial in select patients with severe clinical manifestations (see 'Immunosuppression and plasmapheresis in select patients' above):

-For patients with rapidly progressive glomerulonephritis (RPGN) due to HBV infection, we suggest immunosuppression in addition to antiviral medication (preferably a nucleoside/nucleotide analog) (Grade 2C). In such cases, we usually treat with a short course of glucocorticoids with or without an immunosuppressant, such as cyclophosphamide or rituximab. (See 'Rapidly progressive glomerulonephritis (RPGN)' above.)

-For patients with PAN and severe manifestations (defined by the presence of ulcerative or gangrenous lesions of the extremities, AKI, polyneuropathy, central nervous system involvement, mesenteric arteritis, or myocardial ischemia), we suggest immunosuppression in addition to antiviral medication (preferably a nucleoside/nucleotide analog) (Grade 2C). In such cases, we usually treat with both glucocorticoids and plasmapheresis. (See 'Polyarteritis nodosa (PAN)' above.)

●Patients with concomitant HCV infection – The management of patients with concomitant hepatitis C virus (HCV) infection is complex. The choice of therapy depends upon the state of viral replication of the two viruses. HBV DNA and HCV RNA levels should be measured to help determine the approach to treatment. If HCV RNA is detected, direct-acting antivirals should be administered for treatment of hepatitis C along with antiviral therapy for hepatitis B to prevent HBV reactivation. (See 'Patients with concomitant HCV infection' above.)