Hepatitis B virus (HBV) is probably the most common virus found globally, affecting approximately 400 million subjects worldwide, although its incidence is decreasing due to the vaccination. The most severe complication is the hepatocellular carcinoma (HCC) that represents the ninth cause of death (1). In addition to the hepatic disease, the HBV is a frequent cause of extra hepatic disorders, among which the most common are glomerulonephritis (GN), vasculitis, and arthritis.

HBV may be distinguished in 10 different genotypes; each of them is further divided in several subtypes. Genotypes are distinguished according to alphabetical letters. According to the genotype and subtype, HBV has a different geographical localization and causes different aggressive diseases (2).

Initially, genotype A seemed to be the most frequent cause of glomerular disease (3), but, subsequently, a more accurate study (4) has not confirmed a significant association between HBV genotype and renal disease.

HBV is a member of Hepadnaviridae. HBV genome is represented by a round DNA. There are four genes encoded by the genome: C, X, P, and S. The core protein is encoded by the C gene (HBcAg). The early antigen (HBeAg) is derived from a proteolytic action of gene P. Gene S encodes the surface antigen (HBsAg) (5, 6). The structure of HBV is important to explain its effects and, in particular, different pathogenetic pathways of glomerular disease.

The principal targets of HBV are hepatocytes. According the status of viral replication, different conditions have been described ranging from an immune-tolerant phase to an immune-reactive phase with occurrence of hepatic necrosis and fibrosis. As this phase prolongs or repeats, fibrogenesis develops with subsequent cirrhosis. HCC is a major complication that can occur in the presence or absence of cirrhosis (7).

Extra hepatic manifestations of HBV infection may include dermatological manifestations, such as keratolysis, urticaria, purpura, and lichen planus, systemic diseases, such as serum sickness syndrome, polyarthralgia, polyarthritis, and, most importantly, renal diseases (7, 8). The latter include membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, and focal segmental glomerulosclerosis (FSGS) (9). Less frequently, minimal change disease (MCD) and amyloidosis have been described in association with HBV, although this association is debated. Additionally, polyarteritisnodosa (PAN) is strongly associated with HBV. The disease is characterized by a necrotizing small and medium vessel vasculitis.

Three different factors may contribute to the development of HBV-associated renal diseases:

HBV antigens containing immune complexes

The diagnosis of an HBV-related renal disease should be suspected for any HBV-positive patient with an abnormal urine analysis or a reduced renal function.

Patients with proteinuria, higher than 1 g (24 h), and microematuria are suspected for glomerular lesions. In such cases, a renal biopsy is necessary to confirm the suspected diagnosis (Figure 2). The diagnosis of HBV-related glomerular disease is confirmed by finding monoclonal antibodies and one or more HBV antigens (HBsAg, HBcAg, or HBeAg), although in one study only 39% of biopsies were positive (43). In the case of HBV-related PAN, urine-analysis may be negative, and a definitive diagnosis should be made by angiography (44).

The vast majority of our knowledge on the treatment of HBV-related GNs relies on studies on membranous nephropathy, while data on MPGN or other glomerular diseases principally refer to case reports.

The main goal of the treatment is to reduce viral load. Antiviral treatment is effective in inducing HBV clearance and proteinuria remission (45, 46). In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on glomerulonephritis recommended interferon alpha (IFNα) with nucleos(t)ide analogs (NAs) as the treatment of choice for HBV-GN (47).

Initially, the antiviral treatment was based on IFNα and lamividine (LMV). Their use was effective in reducing proteinuria, principally in children with membranous nephropathy (48, 49). According these studies the renal prognosis was different in children and adults. Indeed, the occurrence of ESRD was 3% in children and 30% in adults.

Main drawback of LMV was the appearance of mutants resistant to therapy (50).

The peginterferon (PEG-IFN) alpha-2a is a more powerful treatment because it has both immune regulatory and antiviral action (51).

IFNα could induce proliferation of T lymphocytes and helper T cells (52).

Patients affected with HBV-related MN have a reduced TCD28-related cytotoxic activity, and IFNα treatment has an effective activity in 30–40% of patients with clearance of HBeAg (53).

Other NAs, in addition to LMV, used to date are entecavir (ETV), adefovir (ADV), telbivudine (TBV), and tenofovir (TAF), although LMV, ADV, and TBV are not recommended for treating chronic HBV infection (54).

ETV is effective with low resistance (55). Its dosage should be reduced according to renal function (56). ADV is effective for liver improvement, viral suppression, and biochemical improvement in patients resistant to LMV (57, 58). A major drawback of ADV is dose-dependent nephrotoxicity that could be avoided by maintaining a dose of 10 mg/daily (59, 60).

Use of TBV is limited due to the emergence of drug resistance that may reach 25.1% in 2 years of treatment (61, 62). Additionally, TBV may cause myopathy and peripheral neuropathy (63).

TAF is a better-known NA and is used as two variants: tenofovirdisoproxil fumarate (TDF) and tenofoviralafenamide (TAF).

TDF is effective on HBV, but is nephrotoxic because of tubular injury (63). Because of this fact, TDF should be avoided in the treatment of HBV-related GN. More promising is TAF, which seems to have a reduced nephrotoxicity with a similar antiviral action (64, 65). TAF seems to have a higher antiviral activity and reduced nephrotoxicity than TDF, though few studies have compared the two drugs.

The WHO (56) recommends the dose reduction of TAF and ETV according to renal function (creatinine clearance) as shown in Table 1.

Although the aim of this study was to review principal treatments for HBV-related GN, briefly we report the conclusions of the Swedish guidelines (66) for the use of PEG-IFN and NAs.

PEG-IFN has a weak antiviral effect compared to NAs. A small number of HBeAg-positive and negative patients obtained HBsAg clearance. In addition, PEG-IFN is poorly tolerated and necessitates parenteral administration.

NAs have a major potency in elimination of virus. ETV, TDF, and TAF are recommended because these drugs have a higher barrier to drug resistance. On the contrary, LMV, ADV, and TBV with low barrier to drug resistance are not recommended.

ETV, whose dose should be reduced according eGFR, is the preferred treatment for naïve, non-cirrhotic HBeAg-positive patients. Attention should be paid to cross-resistance with LMV.

TDF is a highly effect treatment and has been approved as a monotherapy for the treatment of HBV. Risks of renal side effects do exist; hence, renal function should be monitored frequently.

TAF has the same mode of action as that of TDF, with fewer side effects on the kidney, and does not need to be monitored, although not recommended for patients with a very low eGFR.

The Swedish guidelines (66) report the outcomes of different NAs in HBeAg-positive and HBeAg-negative patients (Table 2).

Summarizing, the wider experience of the effects of antiviral treatments in HBV-GN is based on the studies conducted with LMV and IFNα therapy. Studies comparing the efficacy of new NAs and IFNα are still lacking. Anyway, HBV-GN goes into remission with the elimination of viral antigen (67–69). This fact favors the use of NAs with high potency. However, more studies are needed to confirm this point.

Immunosuppressants are also used frequently in the treatment of HBV-GN.

The usefulness of steroids is debated because the inhibition of the immune system may favor HBV replication (70). In a meta-analysis study, the steroid efficacy is not proved (45). In this study, both proteinuria remission and HBeAg clearance were obtained with the use of antiviral agents.

Administration of steroids is not recommended principally in patients with high viral load.

Similarly, the use of rituximab and cytotoxic agents may cause fatal complications (71, 72).

Only in the treatment of HBV-PAN, the association of steroids and plasmapheresis has been used successfully (73).