HBV-GN is an uncommon but a well-described complication of chronic hepatitis B. There is a high incidence of morbidity and mortality although remission with preservation of renal function has been reported[2
]. HBV-GN has been reported from all over the world[10,27-31
], but China is known to be the most endemic area with a high incidence of progressive HBV-GN and poor prognosis in adults[32
]. Case reports and small scale reports have been published, but unfortunately a standardized treatment protocol and justification for the current therapeutic regimen are lacking.
Antiviral drugs have been recommended for treatment of HBV-GN because they can inhibit HBV replication and reduce proteinuria[31,33-35
]. The mechanisms by which antivirals including IFN and the nucleoside analogues, e.g., lamivudine and entecavir, reduce the nephrotic syndrome and decrease the proteinuria are known to be by their viral suppression and HBeAg seroconversion, reduction of serum HBV DNA, normalization of serum alanine transaminase[36
]. On the other hand, the virological features of HBV, i.e., the genotype or viral load, genetic barrier, drug potency, patient adherence, and the duration of HBV infection, could play important roles in viral resistance even with nucleoside analogues that target the HBV DNA polymerase[37
]. For patients who do not respond well to the antiviral therapy or/and have little signs of proteinuria remission, immunosuppressants, especially the glucorticosteroids, are often empirically used in clinics. This is even true for cases treated in developing countries such as China[38
]. In fact, immune complexes have been identified in the kidney indicating that the pathogenesis of HBV-GN may be associated with an immune reaction. This could be supportive for the use of immunosuppressants. However, the use of steroids is still controversial because of the risk of activating viral infections[3
]. In addition, the efficacy of steroids has not been definitively determined.
It has been claimed that HBV-GN occurs predominantly in children and mainly in male patients[39
]. The incidence of male patients has been reported to be about 1.5 to 2 times that of female patients[40
]. Our meta-analysis of 286 adult patients from 10 studies showed that there were 2.4 times more male patients than female patients. Because all of the trials in this study were from China and considering the fact that China has a relatively larger population of men than women (Census Bureau released in 2011: Chinese male to female population ratio = 120:100), our analysis showed a still higher incidence of male patients.
The use of prednisone has been reported to cause a significant increase in the levels of HBeAg and HBV-DNA[5
]. One recent meta-analysis also claimed that glucocorticoid monotherapy did not significantly improve proteinuria[8
]. However, favorable effects of glucocorticoids have also been reported in reduction of proteinuria in MsPGN/MN cases following HBV infection[10
]. In addition, the proteinuria remission rate of HBV-GN after glucocorticoid treatment in adults has been reported to be 75% which is much higher than that for antiviral treatment (28.6%)[10
Our analysis showed that most patients with HBV-GN were successfully treated with combined antiviral and immunosuppressant therapy with an overall estimated rate for proteinuria remission of 83%. Only 2 patients in the treated group dropped out but both were due to economic reasons. Our analyses also demonstrated that the combined therapy can effectively elevate the level of serum albumin. To the best of our knowledge, few reports exist in literature regarding the comparison of combined therapy with monotherapy of either antivirals or immunosuppressants. Thus, it could be an overstatement to conclude that the combined therapy is superior to antivirals or steroids. However, at least our meta-analysis provides evidence showing the efficacy and safety of this combined therapy of antivirals and immunosuppressants, which is actually a widespread practice in China.
Low-dose steroid therapy is aimed at reducing HBV replication while minimizing the risk of HBV activation. Both high-dose and low-dose groups showed similar efficacy of proteinuria reduction following treatment, indicating that low-dose steroid is effective and should be recommended for its safety. In addition, all of the reviewed patients tolerated steroid therapy well without occurrence of liver dysfunction or renal insufficiency.
Our analysis also revealed that no significant increase in the viral titers was observed after combined therapy. However, because the observation time was relatively short, long term effects of the combined therapy should be evaluated in the future.
The most common pathological type of HBV-GN is membranous nephropathy (MN; 50%), followed by MPGN and MsPGN[3
]. Our study of 6 trials (152 patients) showed that MN accounted for 48% and MPGN + MsPGN for 36.8% of the phenotypes of HBV-GN. To determine the efficacy of combined therapy for the different pathological types, the trials were divided into three subgroups: MN, MsPGN, and MPGN. The proteinuria remission rate and complete remission rate were compared between the MN group and the MPGN group. There was no significant difference between the two groups. Comparisons of other pathological types could not be included in this analysis because the number of patients was small. Further studies of larger sample sizes are needed to solve this question.
As with all meta-analyses, our study had some biases. Firstly, negative trials are sometimes less likely to be published. To overcome this, we tried to obtain data from as many sources as possible. We used Funnel plots to test our review for publication bias. The risk of having missed trials was acceptably low. Secondly, the number of high quality clinical trials and number of studied patients were limited. Thirdly, we found that randomization and masking were not satisfactory and the allocation concealment of many studies was not available. Therefore, selection bias cannot be completely ruled out. More adequately powered RCTs with sufficient follow-up periods are definitely needed in future studies. Such RCTs should assess clinically important outcomes such as mortality, long-term relapse rate, and long-term HBV-DNA titer. Furthermore, the antiviral therapy should also be in a standard format in conformity with the APASL guidelines (Seoul 2008)[41
], which would be beneficial for future analysis.
In summary, our meta-analysis of 12 clinical trials showed that combined therapy with antivirals and immunosuppressants is an effective and safe regimen for adult patients diagnosed with HBV-GN. Low-dose steroid is effective and can be recommended.