Renal outcomes of idiopathic and atypical membranous nephropathy in adult Chinese patients: a single center retrospective cohort study.

BACKGROUND: Membranous nephropathy (MN) is mainly classified into idiopathic MN (iMN) and secondary MN in etiology. In recent years, a new kind of membranous nephropathy, atypical membranous nephropathy (aMN) which shows "full house" in immunofluorescence but without definite etiology was paid more attention. In a single center cohort, the renal outcomes of iMN and aMN were compared. METHODS: iMN and aMN patients were selected from renal pathology databank from January 2006 to December 2015. Patients' demographics, laboratory values, induction regimens and patients' responses were recorded. Specially, creatinine, eGFR, albumin and 24 h urinary protein excretion were recorded at 6th month after the induction of immunosuppressive (IS) treatment and at the end of follow up. Complete proteinuria remission was defined as urinary protein < 0.3 g/d, partial proteinuria remission was defined as urinary protein between 0.3 g/d ~ 3.5 g/d and decreased > 50 % from the baseline. The primary outcome was worsening renal function, defined as a 30 % or more decrease in eGFR or end-stage renal disease (eGFR < 15ml/min/1.73m2). COX proportional hazard models were used to test if aMN was a risk factor of worsening renal function compared with iMN. RESULTS: There were 298 patients diagnosed with MN and followed in our center for 1 year or more, including 145 iMN patients with an average follow-up time of 4.5 ± 2.6 years, and 153 aMN patients with 4.1 ± 2.0 years (p = 0.109). The average age of iMN patients was older than aMN patients (56.1 ± 12.2 versus 47.2 ± 16.2 years old, p < 0.001). There were 99 iMN patients and 105 aMN patients with nephrotic range proteinuria and without previous immunosuppressive treatment. 93 (93.9 %) and 95 (90.5 %) patients underwent immunosuppressive treatment in iMN and aMN group, and there was no significant difference of the overall proteinuria remission rates at 6th month (59.1 % vs. 52.0 %, p = 0.334) and endpoint (73.7 % vs. 69.5 %, p = 0.505) between the two groups. 25 (25.3 %) patients in iMN group and 21 (20.0 %) patients in aMN group reached primary endpoint (X2 = 0.056, p = 0.812). Multivariate COX regression showed that after demographics, baseline laboratory values and remission status at 6th month were adjusted, aMN group had similar renal outcome compared with iMN group, the HR of primary outcome was 0.735 (95 % CI 0.360 ~ 1.503, p = 0.399). CONCLUSIONS: The proteinuria remission rates and renal outcomes were similar in iMN and aMN patients after covariables were adjusted.

Interaction between PLA2R1 and HLA-DQA1 variants contributes to the increased genetic susceptibility to membranous nephropathy in Western China.

AIM: Recent studies showed that single nucleotide polymorphisms (SNP) within the phospholipase A2 receptor (PLA2R1) and human leukocyte antigen complex class II HLA-DQα-chain 1 (HLA-DQA1) genes were associated with the susceptibility to patients with primary membranous nephropathy (PMN). However, the results of previous research have not been always consistent. METHODS: We performed a case-control study including 314 patients with PMN and 354 healthy subjects in Western China. Eight SNP in PLA2R1 and one SNP in HLA -DQA1 were genotyped and association between PLA2R1 and HLA-DQA1 was investigated. One hundred and twenty patients were detected anti-PLA2R antibodies to analyze the association between genotype and anti-PLA2R antibody. RESULTS: We found A allele of rs2715918 (odds ratio (OR) = 1.66, corrected P values (Pc) = 7.9 × 10-3 ), A allele of rs4665143 (OR = 1.76, Pc = 2.7 × 10-6 ) and A allele of rs2187668 (OR = 3.29, Pc = 8.0 × 10-11 ) were associated with PMN. Susceptibility of PMN was significantly increased with rs2715918 in dominant model (OR = 1.624, Pc = 5.0 × 10-2 ), rs4665143 in recessive model (OR = 2.134, Pc = 1.4 × 10-4 ) and rs2187668 in dominant model (OR = 3.961, Pc = 4.1 × 10-11 ). The haplotype ATAC of rs2715918, rs6757188, rs4665143, rs3749119 was associated with the high risk of PMN (OR = 1.453, P = 3.0 × 10-4 ). Interaction of rs2715918 GA/AA, rs4665143 GA/AA and rs2187668 GA/AA could significantly increase the 10.61-fold higher risk for the development of PMN (OR = 10.61, P = 4.0 × 10-10 ). Patients who carried with risk genotypes for both HLA-DQA1 and PLA2R1 (87.8%) had antibodies positivity. However, patients who carried low-risk genotypes (41.6%) had antibodies positivity (P = 0.001). CONCLUSION: There are some differences in PLA2R1 distributions in PMN patients between previous literature and our study. Our results showed that interactions between PLA2R1 and HLA-DQA1 alleles increased genetic susceptibility to PMN in Western China.

Analysis of PLA2R1 and HLA-DQA1 sequence variants in Japanese patients with idiopathic and secondary membranous nephropathy.

BACKGROUND: Several recent studies in patients with idiopathic membranous nephropathy (iMN) from Western and Asian counties showed that some single nucleotide polymorphisms (SNPs) within the PLA2R1 and HLA-DQA1 genes are significantly associated with iMN. However, there is only 1 report on analysis of PLA2R1 and HLA regions in Japanese patients with iMN. METHODS: A total of 58 patients with iMN, 26 patients with secondary MN (sMN), and 50 patients with other diseases were enrolled. All patients were Japanese. We selected 6 SNPs within PLA2R1 and 1 SNP within HLA-DQA1, which were significantly associated with iMN in reported white European cohorts, and sequenced these exons using genomic DNA prepared from peripheral mononuclear cells from each patient. We then analyzed differences in PLA2R1 and HLA-DQA1 sequence variants among the 3 groups. RESULTS: Genotypic and allelic frequency distributions for 3 out of 6 SNPs within PLA2R1, rs3749117, rs35771982, and rs2715918 were significantly different between the iMN and control groups. Allelic frequency distributions for SNP rs2187668 within HLA-DQA1 were significantly different between the iMN and control groups. There were no correlations between PLA2R1 and HLA-DQA1 sequence variants and clinical parameters in patients with iMN. There were no significant differences in genotypic or allelic frequency distributions for examined SNPs between the sMN and control groups. CONCLUSIONS: There are some differences in PLA2R1 SNP distributions between previously reported cohorts from other countries and our Japanese cohort of patients with iMN, while there is a significant association between SNP rs35771982 and iMN in most of reported cohorts.

Membranous nephropathy: a retrospective observational study of membranous nephropathy in north east and central London.

BACKGROUND: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. MN is a clinically heterogeneous disease and it is difficult to accurately predict outcomes (including end stage renal failure) at presentation and whom to treat with potentially toxic therapies. We aimed to identify factors predicting outcome in MN in our cohort from two large tertiary London units by undertaking a retrospective data analysis of 148 biopsy-proven MN patients from North East and Central London between 1995 and 2015. METHODS: Review of clinical and biochemistry databases. RESULTS: Surprisingly, patients that reached end stage renal failure (ESRF) had a less severe nephrosis compared to those that did not develop ESRF; serum albumin 33 g/L (3.3 g/dL) versus 24 g/L (2.4 g/dL), p = 0.002 and urinary protein creatinine ratio (uPCR) 550 mg/mmol (5500 mg/g) versus 902 mg/mmol (9020 mg/g), p = 0.0124. The correlation with ESRF was strongest with the presenting creatinine; 215 µmol/L (2.43 mg/dL) compared to 81 µmol/L (0.92 mg/dL), p < 0.0001. Patients presenting with creatinine of >120 µmol/L (1.36 mg/dL; corresponding to an eGFR of ≤60 ml/min in non-Black males) had an increased rate of ESRF and a faster decline. Other traditional risk factors for progression were not significantly associated with ESRF. Black patients presented with higher serum creatinine but no statistically significant difference in the estimated glomerular filtration rate, a higher rate of progression to ESRF and had a poorer response to treatment. CONCLUSIONS: This ethnically diverse cohort does not demonstrate the traditional risk profile associated with development of ESRF. Thus, careful consideration of therapeutic options is crucial, as current risk modelling cannot accurately predict the risk of ESRF. Further studies are required to elucidate the role of antibodies and risk genes.

PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes.

Membranous glomerulopathy (MG) is most commonly caused by autoantibodies directed against the podocyte phospholipase A2 receptor (PLA2R1) and common variants in this gene are associated with MG. Here for the first time, we carried out a large case-control association study (n=1512) of PLA2R-positive and -negative MG to determine the extent of association in these pathologic subtypes. We performed four separate sets of analyses to determine significance of the single-nucleotide polymorphisms (SNPs) and their haplotypes followed by joint analysis and trans-ethnic mapping to increase power. The PLA2R1 SNP rs35771982 was most strongly associated with PLA2R-positive MG (P=1.4 × 10(-14), odds ratio (ORGG)=1.98). The associations of other SNPs in PLA2R1 could be explained because of linkage disequilibrium with the G-allele. Haplotypes in PLA2R1 did not exceed the significance of rs35771982 even after 10 000 permutations. PLA2R1 variants were only associated with PLA2R-positive MG and predominantly in Caucasians. PLA2R1 variants did not associate with MG in African Americans (AA). There was strong epistasis between HLA-DQA1 SNP rs2187668 and the PLA2R1 variant rs35771982. Thus, common variants in the PLA2R1, particularly rs35771982, modulate PLA2R-positive MG with HLA-DQA1 in Caucasians. PLA2R-negative MG especially in AA, may provide a novel opportunity to discover new genes underlying MG.

Long-term outcome and prognostic factors of idiopathic membranous nephropathy in the Chinese population.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is a representative form of nephrotic syndrome in China. Although IMN is thought to run a more benign course in Asian patients than in the Caucasian population, there has been no persuasive study to determine the long-term prognosis and risk factors for IMN in the Chinese population. METHODS: A retrospective chart review. All patients admitted to Nanjing Institution of Nephrology from January 1985 to December 2007 with biopsy-proven IMN were enrolled. The primary outcome was the renal survival rate and risk factors at renal biopsy. RESULT: A total of 217 patients were included in the study, and the overall renal survival rates were 96.9%, 93.5%, and 86.6% at 5, 10, and 15 years after renal biopsy, respectively. When the clinical features at biopsy were evaluated, patients with hypertension (p = 0.023), decreased eGFR (p < 0.001), nephrotic-range proteinuria (p = 0.047), elevated urinary NAG (p = 0.045) and RBP (p = 0.007) had a worse prognosis. Cox multivariate analysis showed that decreased eGFR and chronic tubulointerstitial lesion were independent risk factors for ESRF (end-stage renal failure). CONCLUSION: IMN is a disease with a comparatively good prognosis in the Chinese population, with a renal survival rate of more than 90% at 10 years after renal biopsy. Decreased eGFR at biopsy and chronic tubulointerstitial lesion are independent risk factors of ESRF. Partial or complete remission of proteinuria improved the prognosis.

Anti-phospholipase A2 receptor antibody in membranous nephropathy.

The M-type phospholipase A2 receptor (PLA2R) is a target autoantigen in adult idiopathic membranous nephropathy (MN), but the prevalence of autoantibodies against PLA2R is unknown among Chinese patients with MN. Here, we measured anti-PLA2R antibody in the serum of 60 patients with idiopathic MN, 20 with lupus-associated MN, 16 with hepatitis B (HBV)-associated MN, and 10 with tumor-associated MN. Among patients with idiopathic MN, 49 (82%) had detectable anti-PLA2R autoantibodies using a Western blot assay; an assay with greater sensitivity detected very low titers of anti-PLA2R in 10 of the remaining 11 patients. Using the standard assay, we detected anti-PLA2R antibody in only 1 patient with lupus, 1 with HBV, and 3 with cancer, producing an overall specificity of 89% in this cohort limited to patients with secondary MN. The enhanced assay detected low titers of anti-PLA2R in only 2 additional samples of HBV-associated MN. In summary, these results suggest that PLA2R is a major target antigen in Chinese idiopathic MN and that detection of anti-PLA2R is a sensitive test for idiopathic MN.

Can prognostic factors assist therapeutic decisions in idiopathic membranous nephropathy?

Idiopathic membranous nephropathy (IMN) may have a variable course, with some patients entering spontaneous remission and others slowly progressing to renal failure. The disease is treatable, but the available treatments are not devoid of potential morbidity. We review the studies dedicated to finding prognostic markers. Although a number of clinical and histologic markers are associated with an increased risk of progression to renal failure, in many cases it is still impossible to recognize at presentation what will be the long-term outcome for a patient with IMN. More reliable are time-dependent predictors, such as the amount of proteinuria over time and complete or partial remission. However, this means that a physician should wait for months or even years before taking therapeutic decisions, with the risk of starting after renal or extrarenal complications have already developed. How to proceed will have to be dictated by a careful evaluation of the patient: Taking into consideration not only the risk of renal progression but also the possible extrarenal complications, we suggest starting a "specific" treatment for patients presenting with full-blown nephrotic syndrome or with increasing levels of serum creatinine, while specific treatment is not necessary for asymptomatic patients with subnephrotic proteinuria.

Etiology and clinical characteristics of membranous nephropathy in Chinese patients.

BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria and can be subdivided into idiopathic and secondary classifications. Most patients with MN present with associated systemic diseases that need to be identified before appropriately diagnosing idiopathic MN. However, the cause and clinical characteristics of MN in Chinese patients have not been investigated. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with biopsy-proven MN at the Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. OUTCOME: The diagnosis of idiopathic and secondary MN was based on clinical, initial laboratory, and histological findings. RESULTS: 390 patients with MN were identified from 1985 to 2005. Of 390 patients with MN, 124 (31.8%) had idiopathic MN and 266 had secondary MN (68.2%). Of patients with idiopathic MN, 75 (60.5%) were men and 49 (39.5%) were women. Mean age was 43.9 +/- 13.2 years (range, 14 to 78 years). Common presentations of idiopathic MN were 60.5% with proteinuria (39.5% of whom presented with nephrotic syndrome), 29.8% with hypertension, 17.7% with hematuria, and 0.8% with decreased kidney function. In patients with secondary MN, causes were autoimmune diseases (73.3%), infections (17.7%), tumors (4.5%), and drugs or toxins (4.5%). Systemic lupus erythematosus was the most common autoimmune disease (predominately in younger women). Hepatitis B predominated in younger men. Greater levels of proteinuria were found in patients who presented with drugs or toxins compared with patients with other secondary MNs (P < 0.05). LIMITATIONS: Not all patients underwent all tests, particularly serum tumor markers, hepatitis C virus antibody, and hepatitis C virus RNA tests. CONCLUSION: Proteinuria was a common presentation in patients with idiopathic MN, which was predominately found in middle-aged to elderly men. Secondary MN was more common than idiopathic MN, and most secondary MN diagnoses were secondary to systemic lupus erythematosus and hepatitis B infection.

Circulating Antibodies against Thrombospondin Type-I Domain-Containing 7A in Chinese Patients with Idiopathic Membranous Nephropathy.

BACKGROUND AND OBJECTIVES: Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M-type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations. The prevalence of THSD7A in other populations and their clinical associations deserve further clarification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immunofluorescence assay was performed to investigate anti-THSD7A antibodies in 578 consecutive patients with biopsy-proven idiopathic membranous nephropathy, 114 patients with secondary membranous nephropathy, 64 disease controls, and 20 healthy controls. Glomerular expression of THSD7A antigen was examined by immunohistochemistry. Anti-PLA2R antibodies and glomerular PLA2R expression were also screened. RESULTS: Among the 578 patients with idiopathic membranous nephropathy, 12 (2%) patients were identified as THSD7A-positive: ten patients were THSD7A-positive alone, which accounted for 16% (ten of 64) of PLA2R-negative patients; two patients were dual-positive for both anti-THSD7A and anti-PLA2R antibodies and showed enhanced expression of both antigens colocalized in glomeruli. Among the 114 patients with secondary membranous nephropathy, one among 44 (2%) patients with cancer had anti-THSD7A antibodies, whereas 18 of 44 (41%) had anti-PLA2R antibodies. No anti-THSD7A antibody was detected in other disease controls or healthy individuals. Clinical features were comparable between the patients with and without THSD7A. During follow-up, two patients who achieved remission had a clearance of circulating antibodies against THSD7A, whereas antibodies increased in parallel with proteinuria in a patient with a relapse. CONCLUSIONS: THSD7A-associated membranous nephropathy has a low prevalence in Chinese patients. The double-positive patients suggest dual autoimmune responses.

Biomarkers to detect membranous nephropathy in Chinese patients.

Anti-M-type phospholipase A2 receptor (anti-PLA2R) is a widely accepted biomarker for clinical idiopathic membranous neurophathy (IMN). However, its ability to differentiate between IMN and secondary MN (SMN) is controversial. The objective of this study was to assess clinical MN biomarkers in blood, tissue and urine samples from Chinese patients. In total, 195 MN patients and 70 patients with other glomerular diseases were prospectively enrolled in the study. Participants were followed up for average of 17 months (range 3-39 months). Anti-PLA2R and anti-THSD7A (thrombospondin type-1 domain-containing 7A) were detected only in MN patient sera and not in controls. Serum anti-THSD7A and THSD7A-positive biopsies were detected in 1/18 and 2/18 PLA2R-negative MN cases, respectively. PLA2R and THSD7A were detected in 72.27% and 40% of SMN cases, respectively. While serum positivity for both anti-PLA2R and anti-THSD7A at the time of renal biopsy was specific to MN patients, neither antigen could discriminate between primary and secondary MN. We also found that high urinary levels of retinol binding protein (RBP) predicted poor proteinuria outcomes in study participants. Patients with low or medium urinary RBP levels achieved remission more frequently than those with high RBP.

Efficacy and safety of tacrolimus vs. cyclophosphamide for idiopathic membranous nephropathy: A meta-analysis of Chinese adults.

The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN) were compared in Chinese adult patients using a meta- analysis of the available literatures. Randomized controlled clinical trials (RCTs) of the treatment of primary IMN with TAC or CTX combined with corticosteroids in the English databases PubMed, Embase and Cochrane, as well as Chinese databases, were searched. Qualified studies were subjected to quality assessment and meta-analysis. A total of 8 RCTs, including 359 Chinese patients, were included in the meta-analysis. The complete remission rate and overall remission rate in the TAC treatment group after 6 months of treatment were higher than those in the CTX treatment group. No significant difference in remission rate was found after 12 months of treatment. There was no significant difference in the adverse reaction between the two groups at the 6th or 12th months. TAC-based treatment was associated with a faster response than CTX at the 6th month, but there was no significant difference between the two groups at 12th month in Chinese adults. Further study is needed to evaluate the long-term efficacy and safety of this treatment regimen.

Clinical features and treatment outcome of idiopathic membranous nephropathy in Chinese patients.

We retrospectively studied the clinical course and treatment outcome of idiopathic membranous nephropathy (IMN) amongst 38 Chinese patients (25 male, 13 female, age 51.6 +/- 14.6 years, follow-up duration 58.2 +/- 51.1 months) who presented over a 10-year review period. Eight never received any form of specific treatment (group I), seven received oral corticosteroid alone for 6-9 months (group II), 17 were given corticosteroid plus cyclophosphamide for 6-12 months (group III), and six were treated with methylprednisolone alternating with chlorambucil every other month for 6 months (group IV). No untoward effect from drugs sufficient to alter the dosage used was recorded. After 6 months of treatment, over 50% of patients went into remission: a significant reduction in proteinuria (p = 0.01, 0.01, 0.02) with a corresponding rise in serum albumin levels (p = 0.01, 0.01, 0.04) was observed in groups II, III, and IV, respectively, but not in group I. During follow-up, one patient in each of groups I, III, IV, and two of group II developed renal function deterioration, which correlated with an abnormal presenting serum creatinine. In six group I and eight group III patients who have been followed for at least 5 years, there was progressive reduction in proteinuria in group III (p < 0.05), but not in group I: serum creatinine has remained unchanged in both groups. IMN runs a benign course in Chinese patients in Hong Kong, with 2.6% of patients going into end-stage renal failure during the study period. Contrary to reports in Caucasians, there is similar treatment response to steroid alone or a combination of steroid and cytotoxic agents.

Development of a high resolution melting method for genotyping of risk HLA-DQA1 and PLA2R1 alleles and ethnic distribution of these risk alleles.

Recent studies have demonstrated that alleles at single nucleotide polymorphisms (SNPs) rs2187668 and rs4664308 within genes HLA-DQA1 and PLA2R1, respectively, had a significant impact on the susceptibility to idiopathic membranous nephropathy (IMN). Analysis of the two genomic loci could identify alleles for individuals at risk for IMN. Conventional methods for genotyping are labor intensive, expensive or time consuming. High resolution melting (HRM) is a new technique for genotyping and has the advantages of simplicity, speed, high sensitivity and low cost. Here, we describe genotyping of SNPs rs2187668 and rs4664308 using HRM. In this study, we identified polymorphisms of rs2187668 and rs4664308 in 480 healthy unrelated Chinese volunteers of two ethnic groups from three different geographical areas in China. The two genomic loci were genotyped by HRM using a saturating fluorescent dye SYTO® 9 on 7900 HT and RG 6000 instruments, and were further confirmed by direct DNA sequencing. Three different SNP genotypes were sufficiently distinguished by HRM with mean sensitivity of 98.8% and mean error rate of 1.9%. In addition, the allele frequencies varied greatly based on ethnic or geographic origins. In conclusion, HRM is a rapid, cost efficient, sensitive, suitable technique for genotyping, and simple enough to be readily implemented in a diagnostic laboratory. We believe this will be a valuable technique for determining the genotype of rs2187668 and rs4664308 and for assessing individual susceptibility to IMN.

Triple therapy with single daily dose of cyclosporine in Japanese patients with idiopathic membranous nephropathy.

OBJECTIVE: The optimal therapeutic approach to patients with idiopathic membranous nephropathy (IMN) remains controversial. In this study, we assessed the efficacy of single daily dose cyclosporine (CsA) combined with low-dose prednisolone (PSL) and an angiotensin II receptor blocker (ARB) in patients with IMN. METHODS: We studied 13 nephrotic patients (8 men, 5 women) with IMN diagnosed on biopsy. An initial single daily dose of 2 mg/kg, but not exceeding 150 mg, CsA was given for 12 months, tapered by a 25 mg reduction every 2 months. An initial twice-daily dose of 0.5 mg/kg PSL was given for 2 months and was also tapered. An ARB was given to all patients and the same dosage was used throughout the study. Patients were followed up for 6 to 66 months. RESULTS: Nine patients achieved complete remission at 6.7±2.9 months, and incomplete remission was obtained in the remaining patients. After a follow-up period of 32.7±20.0 months, their serum creatinine and estimated glomerular filtration rate values were similar to baseline levels. The 9 patients who completed the treatment course have not relapsed. Moreover, there were no adverse effects requiring discontinuation of this triple therapy. CONCLUSION: A single daily dose of CsA combined with a low dose of PSL and an ARB in new-onset nephrotic patients with IMN induced a high remission rate of nephrotic syndrome, with a low incidence of relapse and a low risk of adverse effects. The triple therapy and prospective follow-up shows potential as a treatment approach for patients with IMN.

Retrospective characterization of the S open reading frame of HBV isolated from children with membranous nephropathy treated with interferon-alpha2b.

BACKGROUND: A causal relationship exists between HBV infection and membranous nephropathy. The association is especially close in Black children in sub-Saharan Africa. Interferon-alpha2b is commonly used to treat this condition, but is effective in only 30-40% of patients. The reason for the poor response is unknown. The objective of this study was to determine if mutations in the surface gene of HBV isolated from Black children with HBV-associated membranous nephropathy before, during and after interferon treatment, have any effect on treatment response and vice versa. METHODS: HBV DNA was extracted from a responder, a reverter and a non-responder before and after initiation of 16 weeks of interferon-alpha2b treatment. The preS1/preS2/S region was amplified, cloned and sequenced. RESULTS: The preS2 region was the most variable in the reverter and the non-responder, and the S region was the most variable in the non-responder. Phylogenetic analysis showed that the viral population dynamics between the responder and the reverter/non-responder strains differed as a result of mutations in the surface gene. CONCLUSIONS: The presence of mutations in the S region of HBV could be used as predictive markers to differentiate interferon-alpha2b responders from non-responders provided that detailed analysis of further genomes confirms our findings.

Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome.

BACKGROUND AND OBJECTIVES: Standard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo. RESULTS: Nineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab. CONCLUSION: Rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.

Long-term outcome of Chinese patients with membranous lupus nephropathy.

A retrospective analysis of the long-term outcome of patients with membranous lupus nephropathy (MLN) was conducted. One hundred Chinese patients, 90 females and 10 males with a mean age of 32+/-9 years, with systemic lupus erythematosus and biopsy-proven MLN (ISN/RPS2003 classification criteria) were enrolled in this study. The patient and renal survivals were estimated by the Kaplan-Meier method and the risk factors associated with end-stage renal failure (ESRF) were assessed by the Cox proportional hazards regression analysis. The mean follow-up of all patients was 77.6+/-56 months. During follow-up, two patients died. Patient survival at 5 and 10 years was 98%. Renal survival at 5 and 10 years was 96.1% and 92.7%, respectively. Severe tubular-intersticial lesion (HR 66.514), nephrotic range proteinuria (HR 19.159) and refractoriness to treatments (HR 9.834) were independent risk factors for developing ESRF. Three of the six patients with ESRF had severe tubular-interstitial lesions on initial biopsy. Twenty-one patients underwent a repeat biopsy after 33months' (median time) follow-up, eight (38.1%) of these (class V superimposed class IV in 5, class V superimposed class III in 2 and class VI in 1) had transformed and three (37.5%) of them progressed to ESRF. Complications included infection (13%), thrombosis (3%), avascular necrosis (3%), diabetes mellitus (4%) and skin cancer (1%). The rate of patient and renal survival was high in this group of patients with MLN.

Clinical course and outcome of idiopathic membranous nephropathy in Japanese children.

We retrospectively studied 12 Japanese children (8 boys, 4 girls) with idiopathic membranous nephropathy (IMN), aged 2.9-15.8 (mean 7.7) years at onset. All patients were identified through either screening or a routine urinalysis; proteinuria was present in all, haematuria, which was macroscopic in 4, in 11. Three had nephrotic syndrome (NS) at or soon after onset. Stages on electron microscopy, performed in 10 patients, were I in 3, II in 5 and III in 2. Steroids alone or with cyclophosphamide were administered to 5 patients, including the 3 patients showing NS. Complete remission of proteinuria occurred in 8 patients 0.3-1.6 (mean 0.6) years after onset, and proteinuria did not recur. After a follow-up of 1.6-11.6 (mean 5.9) years, these 8 patients were in complete remission and the remaining 4 had only mild proteinuria; none had hypertension or impaired renal function. Thus, we infer that IMN in Japanese children may have a better course and outcome than IMN in non-Japanese children. Based on a comparative study of Japanese (previously reported cases added to ours) and non-Japanese (mostly Caucasian) children with IMN, this was confirmed; it is possible that steroid therapy in Japanese patients is more effective in inducing remission of NS and preserving renal function.