Hepatitis B Virus-associated Glomerulonephritis Patients Research Articles

DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis

BackgroundAberrant DNA methylation patterns, including hypermethylation of key genes that inhibit fibrosis and inflammation, have been described in human kidney diseases. However, the role of DNA methyltransferase 1 (DNMT1) in hepatitis B virus-associated glomerulonephritis (HBV-GN) remains unclear.MethodsWe explored the underlying mechanism by establishing HBV X protein (HBx) overexpressing renal tubular epithelial (HK-2) cells and human podocytes with DNMT1 knockdown. Using RNA-sequencing to determine the downstream targets of DNMT1 and evaluate its levels of promoter methylation. HBV transgenic mice were used to examine the effects of DNMT1 inhibitor on renal in vivo.ResultsDNMT1 was significantly upregulated in the renal tissue of HBV-GN patients, accompanied by injuries of HK-2 cells and podocytes. HBx markedly upregulated DNMT1 and induced epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells and human podocytes. This increased DNMT1 expression was attenuated after DNMT1 knockdown, accompanied by restored HK-2 cells and podocyte injuries resulting from the activation of PI3K/Akt/mTOR and nuclear factor-kappa B (NF-κB) pathways. Hypermethylation of the phosphatase and tensin homolog (PTEN) promoter and vitamin D receptor (VDR) was induced in HBx-overexpressing HK-2 cells and podocytes, respectively, whereas DNMT1 knockdown effectively corrected these alterations. Furthermore, PTEN and VDR ablation resulted in marked EMT and inflammation induction in HBx-overexpressing HK-2 cells and human podocytes even with DNMT1 knockdown. Downregulation of the PI3K/Akt/mTOR-related pathway attenuated HBx-induced EMT and inflammation in HK-2 cells. Luciferase reporter assay revealed VDR as a direct target of the Snail family transcriptional repressor 1 (SNAI1) in HBx-overexpressing podocytes. DNA methylation inhibitor 5-azacytidine alleviated urinary protein and renal inflammation in HBV transgenic mice via PTEN-PI3K/Akt signaling and VDR signaling axis.ConclusionsOur study clarifies the potential epigenetic mechanisms underlying HBx-induced renal injuries in HBV-GN and the renoprotective effects of inhibiting DNMT1, which can provide important insights into the development of treatments for HBV-GN.

The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.

The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. ClinicalTrials.gov Identifier NCT03062813.

Hepatitis B Virus-Related Glomerulonephritis with Positive and Negative Serum HBsAg: Different Clinicopathologic Characteristics of Two Clinical Subtypes.

IntroductionThe clinicopathologic characteristics of Hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with different serum HBsAg are not well known. This study aims to investigate the characteristics and treatments between HBV-GN patients with positive and negative serum HBsAg.MethodsA retrospective review of patients with renal biopsies in Guangdong Provincial People’s Hospital from 2005 to 2018 was performed. Clinicopathological data, treatments and remission of proteinuria were collected and compared between HBsAg+ and HBsAg- group.ResultsA total of 101 HBV-GN were recruited. Serum HBsAg+ and HBsAg- patients accounted for 62.4% and 37.6%, respectively. HBsAg+ group had poor kidney and liver functions. Pathological data showed the percentage of membranous nephropathy in HBsAg- group is significantly higher than that of HBsAg+ group (60.3% HBsAg+ vs 89.5% HBsAg-, P<0.05). Chronic renal tubular/interstitial injury was more prevalent in HBsAg+ group (16.9% HBsAg+ vs 2.6% HBsAg-, P<0.05). The deposition sites of immune complexes were significant different between the two groups. In addition, more HBsAg+ patients were given anti-HBV and less were given corticosteroid or immunosuppressants for treatment than that of HBsAg- patients. Percentages of clinical remission were increasing in both HBsAg+ and HBsAg- patients from 1, 3, 6 months to 1 year (18.75%, 45.2%, 67.8%, 82.4% vs 24.4%, 41.2%, 62.8%, 59.3%). The differences of remission betwen two groups were not significant (P>0.05).ConclusionThe clinicopathological characteristics and treatments of HBV-GN with serum HBsAg+ and HBsAg- were distinct, which indicated that the pathogenesis might be different and specific treatments were needed for HBV-GN patients with different serum HBsAg.

Role of histone demethylase KDM6B in HBx-mediated podocyte-macrophage transdifferentiation

Objective: To explore the expression of lysine (k)-specific demethylase 6B (KDM6B) in the renal tissues of hepatitis B virus-associated glomerulonephritis (HBV-GN) patients and human podocytes transfected with hepatitis B virus X (HBx) gene, and its role in HBx-mediated podocyte-macrophage transdifferentiation (PMT). Methods: Forty-eight patients diagnosed as HBV-GN by renal biopsy from 2013 to 2018 at the Shanghai Jiaotong University Affiliated First People's Hospital were included in this study. Thirty patients with primary glomerulonephritis (PGN) and fifteen patients with renal tumor were chosen as control group. The expression of KDM6B and macrophage marker F4/80 in renal tissues of HBV-GN patients was observed by immunofluorescence and immunohistochemistry. The association between kidney KDM6B levels and clinical features of HBV-GN patients was analyzed. The expression of KDM6B, F4/80, major histocompatibility complex (MHC)-Ⅱ and CD40 in the podocytes was detected by Western blotting. The contents of interferon-γ (IFN-γ) and interleukin-6 (IL-6) in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The small interfering RNA of KDM6B (KDM6B siRNA) was used to silence the expression of KDM6B and the protein levels of KDM6B, F4/80 and tri-methylation of lysine 27 of histone H3 (H3K27me3) induced by HBx gene transfection were detected by Western blotting. Results: Renal KDM6B expression was significantly increased in HBV-GN patients compared to normal control (0.022±0.004 vs 0.006±0.002, P=0.006). There was no significant difference in the positive rate of KDM6B among different pathological types of HBV-GN (P=0.139). Moreover, co-expression of KDM6B and F4/80 could be observed in the podocytes of HBV-GN patients. Patients with estimated glomerular filtration (eGFR)<60 ml·min-1·(1.73 m2)-1or proteinuria ≥ 3.5 g/day had a significantly higher renal KDM6B expression compared to control groups (all P<0.05). In addition, the expression of KDM6B, F4/80, MHC-II and CD40 was significantly up-regulated in the podocytes transfected with HBx gene (all P<0.05). The content of IFN-γ and IL-6 in the supernatant was significantly increased (all P<0.05). After gene silencing of KDM6B, the expression of F4/80 induced by HBx in the podocytes was significantly down-regulated, while the level of H3K27me3 was significantly increased (both P<0.05). Conclusions: HBx could induce KDM6B expression in podocytes and initiate PMT, thereby involving in the dysfunction of immune microenviroment in the renal tissues of HBV-GN.

Efficacy and Safety of Long-Term Corticosteroid Monotherapy in 26 Cases of Nephrotic Syndrome with Biopsy-Proven Membranous Nephropathy Induced by Seronegative Hepatitis B Virus-Associated Glomerulonephritis

Background: Hepatitis B virus-associated glomerulonephritis (HBV-GN) can occur in patients with negative HBV serological antigens. Little is known about the treatment of seronegative HBV-GN (sn HBV-GN). The aim of this prospective study was to evaluate the efficacy and safety of corticosteroids in the treatment of sn HBV-GN. Methods: Twenty-six patients with nephrotic syndrome induced by seronegative HBV-associated membranous nephropathy were enrolled. The patients were given methylprednisolone (0.8 mg/kg/day) for 12–24 weeks, tapered by a 2-mg reduction every 1–3 months. Patients were followed up for 6–36 months. Complete remission (CR) was defined as proteinuria <0.3 g/24 h. Partial remission (PR) was defined as proteinuria of 0.3–3.5 g/24 h that was reduced ≥50% of the baseline level. Results: The effective remission (including CR and PR) rates of nephrotic syndrome were 23.1%, 61.5%, 73.1%, 76.2%, 90.5%, and 81.0%, respectively, after 1, 3, 6, 12, 24, and 36 months. Nineteen patients achieved effective remission after 11.68 ± 7.15 months. The level of serum albumin improved from 24.34 ± 6.71 g/L at baseline to 39.61 ± 7.45 g/L at the 36th month significantly. After treatment, the level of serum Cr was similar to the baseline. Only 2 patients relapsed. The primary adverse reaction was infection. None of the patients showed evidence of HBV replication. Conclusion: The long-term middle-dose corticosteroid therapy without antiviral drugs is effective and safe for membranous sn HBV-GN patients. For sn HBV-GN patients, the monitoring of HBV DNA and HBV markers in the serum is necessary during the corticosteroid monotherapy. Trial Registration: The Chinese Clinical Trial Registry (ChiCTR1900022518).

Severity of Intrarenal Arterial Lesions Can Predict the Clinical Prognosis of Hepatitis B Virus-Associated Glomerulonephritis: A Retrospective Study

Background: Intrarenal arterial lesions (IALs) have been studied in immunoglobulin A nephropathy and lupus nephritis, but this has not been reported in hepatitis B virus-associated glomerulonephritis (HBV-GN). This study aims to investigate the prevalence and the role of IALs in HBV-GN. Methods: IALs were examined in kidney biopsy specimens from 205 patients with HBV-GN retrospectively. The severity of IALs and tubular interstitial lesions was scored semi-quantitatively. The severity of IALs was divided into 4 groups on the basis of ILA score, which were no IALs (Score 0), mild IALs (Score 1–2), moderate IALs (Score 3–4), and severe IALs (Score 5–10) groups. Survival analysis was performed using the Kaplan-Meier method between the severity of IALs and clinical events (doubling of serum creatinine [SCr], ESRD, and death due to the kidney disease). Results: Among 205 patients with HBV-GN, 143 (69.8%) had IALs in their kidney biopsy specimens. IALs were mild in 28 (19.6%) patients, moderate in 101 (70.6%) patients, and severe in 14 (9.8%) patients. The severity of IALs was associated with high blood pressure (BP), high SCr, and severe tubulointerstitial injuries. The average follow-up time of these 205 HBV-GN patients was 94.2 ± 47.1 months, in which 46 cases had clinical event. The proportions of clinical events in no IAL, mild IAL, moderate IAL, and severe IAL groups were 9.7, 14.3, 25.7, and 71.4%, respectively. Event-free survival of patient in IAL group was significantly lower than that in the no IAL group (p = 0.000). Multivariate cox regression analysis indicated SCr (1.011, 1.007–1.016), hypertension (1.767, 1.004–3.108), and IAL (2.194, 1.062–4.530) were independent risk factors for clinical events after adjustment for age and gender. Event-free clinical survival in moderate and severe IAL groups was significantly lower than that in the no IAL group (p = 0.0111 and p = 0.0001, respectively). Besides, event-free renal survival in severe IAL group was significantly lower than that in moderate IAL group (p = 0.009). Multivariate cox regression analysis showed that the more severe the IALs, the higher the risk of the clinical event, with a hazard ratio of 2.284 for moderate IALs (1.085–4.907) and 3.315 for severe IALs (1.296–8.482). Conclusions: Severity of IALs is associated with high BP, reduced renal function, and poor clinical prognosis in HBV-GN patients.

The histone demethylase LSD1 promotes renal inflammation by mediating TLR4 signaling in hepatitis B virus-associated glomerulonephritis

Renal inflammation significantly contributes to the progression of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN), but the mechanisms that control its precise regulation remain largely unknown. In this study, we showed that the lysine-specific demethylase 1 (LSD1) was significantly upregulated in renal tissue of HBV-GN patients, and its expression was positively correlated with inflammation. Functionally, LSD1 could promote HBV-induced release of proinflammatory mediators in HK-2 cells, a human renal tubular epithelial (RTE) cell line. Mechanistic investigations suggested that LSD1 directly promoted the transcription of the inflammatory-related gene Tlr4 by eliminating the mono- or di-methylation of H3K9 near its promoter. Knockdown of Lsd1 further inhibited TLR4-NF-κB/JNK signaling cascades, and subsequently decreased HBV-induced production of proinflammatory mediators in HK-2 cells. Co-transfection with Tlr4-expressing plasmids counteracted these effects. Meanwhile, downregulation of abovementioned TLR4-related pathways using small-molecule inhibitors attenuated inflammation. Importantly, LSD1 inhibitor tranylcypromine (TCP) could inhibit TLR4-NF-κB/JNK signaling axis and alleviate renal inflammation in HBV transgenic mice. Taken together, our data identify LSD1 as a novel regulator of renal inflammation and as a potential therapeutic target in HBV-GN.

Effectiveness of telbivudine antiviral treatment in patients with hepatitis B virus-associated glomerulonephritis: A 104-week pilot study.

The aim of this study was to evaluate clinical efficacy of telbivudine in treatment of hepatitis B virus-associated glomerulonephritis (HBV-GN).A total of 43 HBV-GN patients combined with chronic hepatitis B were treated with telbivudine for 104 weeks. Serum levels of HBV DNA viral load, HBeAg, HBeAb, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Cr), and 24-hour urinary protein were evaluated after telbivudine treatment of 12, 24, 52, 76, and 104 weeks. Estimated glomerular filtration rate (eGFR) was calculated at baseline, 24 weeks, 52 weeks, and 104 weeks of treatment, respectively. Complete remission (CR) was defined as urinary protein <0.3 g/day, with normal ALT, AST, Cr, and eGFR. Criteria for partial remission include: 24-hour urinary protein excretion decreased by >50% compared with baseline level, and ALT and AST decreased >50%.Proteinuria level gradually decreased in patients with HBV-GN after telbivudine treatment. The percentages of PR + CR were 90.7% and 95.3%, respectively, at 52 and 104 weeks. Compared to baseline, eGFR were significantly increased from 69.2 ± 23.1 mL/min/1.73 m2 to 116.2 ± 26.3 mL/min/1.73 m2 at 104 weeks of treatment. Multivariate analysis indicated that baseline HBV DNA viral load (odds ratio [OR] = 1.19, 95% confidence interval [CI] 1.11–2.19, P = .02) and baseline urinary protein (OR = 1.08, 95% CI 1.04–2.44, P = .03) were independent risk factors associated with CR after telbivudine treatment among patients with HBV-GN.Our study demonstrates that telbivudine can be used to treat HBV-GN and effectively improve eGFR in these patients.

Meta-analysis of the efficacy and safety of nucleotide/nucleoside analog monotherapy for hepatitis B virus-associated glomerulonephritis.

Antiviral monotherapy is recommended for hepatitis B virus-associated glomerulonephritis (HBV-GN) treatment. Although considered superior to interferon-α in several respects, nucleotide/nucleoside analog (NA) monotherapy has not been studied. This metaanalysis evaluates the efficacy and safety of NA monotherapy for treating HBV-GN. We searched for controlled clinical trials of NA monotherapy for HBVGN in the MEDLINE, Embase, Cochrane Library, Chinese BioMedical Literature on disc, Chinese National Knowledge Infrastructure, and Wanfang databases. Primary outcome measures were proteinuria remission, HBV-DNA negative conversion rate, and hepatitis B e-antigen (HBeAg) clearance. Secondary outcome measures were variations in proteinuria, serum albumin, alanine aminotransferase (ALT), and serum creatinine (Scr). Ten trials involving 325 patients were included: four randomized controlled trials, two cohort clinical trials, and four self-controlled studies. Based on the fixed-effects model, we found significant proteinuria remission rate improvement in the NA group (relative risk (RR): 3.60, 95% confidence interval (CI): 1.99 – 6.50), negative conversion rate of HBV-DNA (RR: 2.20, 95% CI: 1.55 – 3.13), and clearance of HBeAg (RR: 4.49, 95% CI: 1.29 – 15.67). Improvement in ALT (mean difference (MD): 56.60, 95% CI: 50.41 – 62.79) was found with the fixedeffects model, and a slight decrease in Scr (MD: 25.25, 95% CI: –17.11 – 67.61, p = 0.24) was shown. HBV-GN proteinuria remission with elevated serum albumin, decreased HBV replication, and improved HBeAg clearance could be achieved using NA monotherapy. Furthermore, NA monotherapy may protect renal function in HBV-GN patients by preventing Scr elevation.

Hepatitis B virus-associated glomerulonephritis in HBsAg serological-negative patients.

The main objective of this study is to report the clinical and pathological characteristics of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN) in serum hepatitis B surface antigen (HBsAg)-negative patients in China. HBV-GN is caused by the HBV's attack on the kidney tissues, but definitive diagnostic criteria are still lacking. The diagnostic criteria used in China require HBsAg positivity in the serum, but research on occult HBV infection has shown that HBV infection is also found in serum HBsAg-negative patients. Clinical and pathological characterization of HBV-GN in serum HBsAg-negative patients is required. Serologic and clinical findings and pathological characteristics of renal tissues in 18 HBV-GN patients (11 men and seven women) with serum HBsAg negativity were analyzed retrospectively. Thirty-three HBV-GN patients with serum HBsAg positivity and 59 patients with membranous nephropathy (MN) without any HBV infection markers in serum and renal tissues during the same period were included as controls. Among the 18 HBsAg-negative patients with GN, 12 had HBsAb positivity in their sera. None of the patients was positive for serum HBeAg. Proteinuria was the major clinical manifestation and the renal histopathology was characterized as MN. Immune fluorescence deposits in renal tissues consisted mainly of HBsAg. The degree of renal injury and the decrease in the C3 level were less than those in HBsAg-positive patients and idiopathic membranous nephropathy patients. We propose to use the HBV marker in renal tissues as a new diagnostic criterion for HBV-GN. If MN patients have HBV marker positivity in renal tissues, HBV-GN can be diagnosed even without HBsAg in the serum. This would improve the diagnostic accuracy and potential treatment efficiency.

Study on Hyperuricemia in HBV-Associated Glomerulonephritis

To determine the prevalence and risk factors for hyperuricemia in hepatitis B virus-associated glomerulonephritis (HBV-GN). Univariate and multivariate logistic regression analysis was applied to decide the risk factors of hyperuricemia in HBV-GN, and clinical and pathologic data were compared between HBV-GN patients with hyperuricemia and those with normal serum uric acid. Among our 227 HBV-GN cases, 31.3% of the patients had hyperuricemia at the time of renal biopsy. Univariate analysis showed that the level of serum creatinine and the severity of glomerular and tubular interstitial injury were significantly related to hyperuricemia. Multivariate logistic regression analysis identified the levels of serum creatinine and tubular interstitial injury as independent factors for hyperuricemia. The incidence of hypertension and lower estimated glomerular filtration rate was significantly higher in hyperuricemic patients with HBV-GN than in normouricemic patients. There were also fewer membranous nephropathy, more proliferative sclerosing glomerulonephritis, and more tubular interstitial injury in hyperuricemic patients with HBV-GN. Our study results suggest that hyperuricemia is common in HBV-GN, which may facilitate the progression of HBV-GN and renal tubular interstitial injury as well as the development of hypertension.

Expression of AIM2 is high and correlated with inflammation in hepatitis B virus associated glomerulonephritis

Background & aimsInnate immunity is the first line of defense against invasive microbial infection, and AIM2 plays an important role in this process by sensing double-stranded DNA viruses. However, the role of AIM2 in regulating the immune response to viruses in vivo, especially in sensing hepatitis B virus (HBV), has not been examined. We hypothesized that the expression of AIM2 increases corresponding to HBV-mediated inflammation in patients with hepatitis B virus associated glomerulonephritis (HBV-GN), a condition which activates inflammatory mechanisms and causes renal damage. To test this hypothesis, we analyzed the expression of AIM2 in HBV-GN patients in relation to the inflammatory response to HBV infection.MethodsA total of 79 patients diagnosed with chronic nephritis (CN) were enrolled in this study, including 54 HBV-GN patients as the experimental group and 24 chronic glomerulonephritis (CGN) patients as the negative control group. Six patients diagnosed with chronic hepatitis B (CHB) were also enrolled as positive controls. Each CN patient received renal biopsy, and immunohistochemistry was used to detect the expression of AIM2 and inflammatory factors caspase-1 and IL-1β in the biopsy specimens. CHB patients received liver puncture biopsy, and immunohistochemistry was used to detect the expression of AIM2 in these specimens. Expression of AIM 2 among different groups and in relation to inflammatory factors caspase-1 and IL-1β was analyzed.ResultsThe expression of AIM2 in HBV-GN patients (81.4%) was significantly higher than in CGN patients (4.0%). Among the HBV-GN patients, expression of AIM2 was significantly higher in the high HBV replication group than in the low HBV replication group. AIM2 expression was not correlated with age, gender, HBeAg status in serum, HBV-antigen type deposited in renal tissue or pathological type of HBV-GN. However, AIM2 levels were positively correlated with the expression of caspase-1 and IL-1β in HBV-GN patients. The data suggest that AIM2 expression is directly correlated with HBV infection-associated inflammation.ConclusionThe elevation of AIM2 during HBV infection or replication may contribute to its associated inflammatory damage, thus providing a putative therapeutic target and a new avenue for researching the pathogenesis of HBV-GN.

Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis

To investigate the efficacy and safety of combined antiviral and immunosuppressant therapy in adult hepatitis B virus-associated glomerulonephritis (HBV-GN) patients. A computerized literature search was carried out in the PubMed database, Embase, the Cochrane Library, Chinese BioMedical Literature on disc, Chinese Medical Current Contents, Chinese National Knowledge Infrastructure, Wanfang and VIP (Chinese Technological Journal of Database) to collect articles between June 1980 and December 2010 on therapy with immunosuppressants, e.g., glucorticosteroids, mycophenolate mofetil and leflunomide, combined with antivirals, e.g., interferon, lamivudine, entecavir and adefovir dipivoxil, in adult HBV-GN patients. The primary outcomes were remission of proteinuria, clearance of HBV e-antigen, and elevation of serum albumin. The secondary outcomes were blood levels of alanine aminotransferase, serum creatinine, and HBV-DNA titer. Meta-analysis was performed using Review Manager 5.1. Fixed or random effect models were employed to combine the results after a heterogeneity test. The effects of the combined therapy were analyzed for different doses of glucorticosteroid and different types of HBV-GN. Twelve clinical trials with 317 patients were included. A significantly higher incidence of HBV-GN was found in male patients (relative risk = 2.40, 95% CI: 1.98-2.93). Combined therapy reduced the proteinuria significantly with a mean difference of 4.19 (95% CI: 3.86-4.53) and increased the serum albumin concentration significantly with a mean difference of -11.95 (95% CI: -12.97-10.93) without significant alterations of liver function (mean difference: 4.62, 95% CI: -2.55-11.79) and renal function (mean difference: 10.29, 95% CI: 0.14-20.45). No significant activation of HBV-DNA replication occurred (mean difference: 0.12, 95% CI: -0.37-0.62). There was no significant difference between the high dose glucorticosteroid group and the low dose glucorticosteroid group in terms of proteinuria remission (P = 0.76) and between different pathological types of HBV-GN [membranous glomerulonephritis (MN) vs. mesangial proliferative glomerulonephritis, P = 0.68; MN vs membranoproliferative glomerulonephritis, P = 0.27]. Combined antiviral and immunosuppressant therapy can improve the proteinuria in HBV-GN patients without altering HBV replication or damaging liver and renal functions.

Treatment of hepatitis B virus-associated glomerulonephritis: A meta-analysis

To evaluate the efficacy of antiviral or corticosteroid treatment on hepatitis B virus-associated glomerulonephritis (HBV-GN). Six and five trials were used respectively to evaluate the efficacy of either antiviral or corticosteroid treatment on HBV-GN. Pediatric patients were pooled separately to assess their response to the above treatment modalities. The primary and secondary outcomes were remission of proteinuria and clearance of Hepatitis B e-antigen (HBeAg), respectively. A fixed or random effect model was established to collect the data. The remission rate of proteinuria (RR = 1.69, 95% CI: 1.08-2.65) and the clearance rate of HBeAg (RR = 6.44, 95% CI: 3.11-13.35) were significantly higher in antiviral treatment group than in control group. The proteinuria remission was significantly associated with HBeAg clearance (P = 0.002). However, the difference in proteinuria remission rate was not statistically significant between corticosteroid treatment group and control group (RR = 1.45, 95% CI: 0.68-3.11). Antiviral therapy could significantly promote the HBeAg clearance in pediatric patients, but neither antiviral nor corticosteroid therapy could significantly decrease proteinuria in pediatric patients compared to controls. Antiviral but not corticosteroid treatment can decrease proteinuria and promote HBeAg clearance in HBV-GN patients.

Two subtypes of hepatitis B virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans.

Hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN) is occurring at high prevalence in most Asian endemic areas. There have been some reports on human leucocyte antigen (HLA) associations with HBV infections; however, HLA association with HBV-GN has been rarely reported. Forty-six adult Korean patients with HBV-GN (42 male and four female patients, age 20-66), 100 HBsAg (-) healthy controls, and 89 individuals with chronic HBV infection were studied for HLA-DRB1 and DQB1 gene polymorphisms using high-resolution DNA typing methods. In HBV-GN patients, a strong association with HLA-DR2 was observed compared with HBsAg (-) controls (OR = 4.0). Different HLA-DR2 alleles were associated with different pathologic subtypes of HBV-GN: DRB1*1502 with membranoproliferative glomerulonephritis (MPGN, n = 35) (OR = 14.5) and DRB1*1501 with membranous nephropathy (MN, n = 11) (OR = 3.8). HLA-DQB1*0601, strongly linked to DRB1*1502, was also associated with MPGN subtype of HBV-GN (OR = 4.3). All these associations were also significant compared with chronic HBV infection group. For chronic HBV infection per se, DRB1*1302, DQB1*0402, and DQB1*0604 had some protective effect (OR = 0.4, OR = 0.3, and OR = 0.1, respectively), and DRB1*1101 was weakly associated (OR = 4.6) in Koreans. These results suggest that HLA-DR or related genetic factor is associated with disease susceptibility to HBV-GN in Koreans, and different pathologic subtypes of HBV-GN are influenced by the genetic factors of the patients.