Hepatitis B virus associated focal and segmental glomerular sclerosis: report of two cases and review of literature

The hepatitis B virus (HBV) is estimated to have infected about 350 million people worldwide, making it one of the most common human pathogens. Renal involvement is among its most common extra hepatic manifestations and usually manifests in the form of immune complex mediated glomerulopathy, such as membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), mesangioproliferative glomerulonephritis and immunoglobulin A (IgA) nephropathy. Occurrence of focal and segmental glomerular sclerosis (FSGS) with HBV infection is rare and only five cases have been reported earlier. We report two cases of hepatitis B associated FSGS. In both the cases, HBsAg was demonstrated in the renal tissue and both the cases showed response to treatment with lamivudine, thus indicating a possible causal association between the viral infection and occurrence of nephrotic syndrome.     

Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab

A 22-year-old patient whose primary kidney disease was focal segmental glomerulosclerosis (FSGS) developed severe recurrence of proteinuria (up to 57 g/24 h) immediately after a haploidentic living donor kidney transplantation despite pre-operative plasmapheresis. The immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil, basiliximab and steroids. He underwent 10 plasmapheresis sessions in the first 3-week post-transplantation. In addition, he received 2 i.v. doses of rituximab (RTX) 600 mg (375 mg/m(2)) on days 7 and 15. Proteinuria decreased below nephrotic range at day 14 and serum creatinine returned progressively to normal values. A short course of oral ciclophosphamide (100 mg/j) was administrated between days 22 and 40 and three additional plasmapheresis sessions on days 34, 39 and 49. This strategy allowed obtaining sustained full remission of the nephrotic syndrome (NS) and excellent graft function, which persists over 2 years after transplantation. No notable adverse events related to RTX or plasmapheresis were observed. This case suggests that RTX associated with plasmapheresis may be an effective treatment of recurrent NS because of FSGS.     

原发性局灶节段性肾小球硬化患者ACTN4基因变异和多态性

目的 了解ACTN4基因变异和多态性在原发性局灶节段性肾小球硬化（FSGS）发病中的作用。 方法 选取FSGS患者82例，另设70例健康人作为对照组。盐析法提取外周血基因组DNA，PCR扩增后测序，与基因数据库进行匹配，寻找可能致病变异位点。氯酚法提取患者父母头发DNA，间接免疫荧光法检测患者肾组织辅肌动蛋白4(α-actinin-4)表达水平。单核苷酸多态（SNP）位点经Hardy-Weinberg平衡检验后行基因频率、基因型和临床表型关联分析。 结果 发现1例患者单核苷酸变异184T>A(Ser62Thr)，1例5’UTR变异1-34C>T。对照组和患者父母未发现相同变异。1个疾病易感SNP位点484+87C>G。变异者肾组织α-actinin 4表达水平分别较对照组和非变异FSGS组下降。变异基因型和野生基因型尿蛋白量（24 h）的差异有统计学意义[（7.90±1.60 ）比(4.50±0.46) g/24 h， P ＜ 0.01]。此外，还发现6个新的变异和另1个SNP位点，但未引起氨基酸改变。 结论 原发性FSGS患者中存在ACTN4基因变异位点和疾病易感SNP位点。ACTN4基因变异在原发性FSGS发病中可能起重要作用。     

Recurrent nephrotic syndrome in a renal allograft recipient with focal and segmental glomerulosclerosis: Efficacy of plasmapheresis

Summary: We report a 29-year-old man with renal failure due to focal and segmental glomerulosclerosis (FSGS) who received a well-matched cadaveric renal allograft and had the early appearance of the nephrotic syndrome and renal insufficiency. His condition responded dramatically to plasmapheresis. the pathogenesis of FSGS recurring in a renal allograft may involve a recently identified circulating factor. the possible efficacy of plasmapheresis in the treatment of recurrent FSGS may be attributable to the removal of this factor.     

Urinary proteome and potential biomarkers associated with serial pathogenesis steps of focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a chronic nephropathy showing characteristic glomerular sclerosis. So far, the diagnosis and prognosis of FSGS rely mainly on the invasive biopsy. Searching for potential FSGS-associated urinary biomarkers representing pre-sclerotic and serial sclerotic stages of FSGS could be helpful to the non-invasive diagnosis and prognosis of FSGS. METHODS: In the present study, we used a 2D gel-based proteomic approach to identify urinary proteins at pre-sclerotic and different sclerotic stages of an FSGS mouse model in order to find FSGS-related urinary proteins. The FSGS mouse model was established in Balb/c mice by a single injection of adriamycin, and disease severity was monitored by renal biological parameters and histopathological features. Urine was collected on days 0, 4, 7, 11, 15 and 20, and subjected to two-dimensional electrophoresis (2-DE) analysis. Proteins were identified by matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS) and a protein database search. Some of the identified proteins were confirmed by western blot analysis. RESULTS: We identified 37 urinary proteins showing characteristic patterns of dynamic changes along the disease course of FSGS. Early urinary proteins appearing before glomerular sclerosis were noticed. Importantly, 11 urine proteins are novel to FSGS and have known functions highly associated with different pathogenetic steps of the disease, including haemodynamic disturbance, podocyte apoptosis, ECM-protein deposition and glomerular sclerosis. CONCLUSIONS: Some urinary proteins appearing earlier than glomerular sclerosis could serve as potential early diagnostic biomarkers. The proteins with the pathogenic roles could serve as potential non-invasive prognostic markers of FSGS, and give an insight into pathogenic mechanisms of this sclerosis disease.     

肾小球上皮细胞增生病变在局灶节段性肾小球硬化症中的临床意义及其组织来源探讨

目的 探讨特发性局灶节段性肾小球硬化症（FSGS）的肾小球上皮细胞增生病变（glomerular epithelial proliferative lesion,GEPL）的临床意义及其组织学来源。 方法 2000年1月至2005年12月间在本研究所接受治疗的特发性FSGS患者共74例,按照是否存在GEPL病变分为两组：GEPL组31例,非GEPL组43例。分析两组患者的临床病理特点,对其活动性及慢性化病理改变进行半定量评估,并对患者的治疗和预后进行随访。通过免疫组化方法分析肾小球增生上皮细胞的细胞表型表达情况。 结果 与非GEPL组相比,GEPL组的病程显著较短（P < 0.05）;肾病综合征（NS）患者比例显著较高（P < 0.05）;节段性硬化的肾小球比例显著较高（P < 0.05）;病理活动性评分显著较高（P < 0.05）;慢性化评分显著较低（P < 0.05）。29例随访患者中,GEPL组（16例）的肾脏存活率明显降低（P ＝ 0.049）。COX回归分析发现GEPL和Scr水平是导致肾衰竭的危险因素（OR值分别为1.204和1.008）。免疫组化结果显示肾小球增生上皮细胞WT-1及Pcx表达缺失;细胞增殖核抗原（PCNA）、Pax-2和CK-8表达阳性。 结论 特发性FSGS的肾小球上皮细胞增生病变是急性期、活动性病变的病理表现,也可能为临床病情较重和肾脏存活预后不良的病理学指征。增生的肾小球上皮细胞缺乏足细胞表型,说明可能源于壁层上皮细胞,但不排除损伤的足细胞去分化、增生并表达壁层上皮细胞标记的可能。     

迟发性家族性局灶节段肾小球硬化的足细胞分子基因突变研究

目的 了解迟发性家族性局灶节段肾小球硬化（FSGS）的足细胞分子基因致病突变特点。 方法 研究对象为上海瑞金医院肾脏科1997年9月至2007年10月收集的31个迟发性家族性FSGS家系。诊断标准：（1）成员年龄大于12岁；（2）1个家系中有2例或2例以上患者经肾活检证实为FSGS，或家系成员中有1例肾活检证实为FSGS，另有1例成员有蛋白尿或肾功能不全。100例健康人为对照组。外周血基因组DNA 经PCR扩增后直接对NPHS2、ACTN4、TRPC6基因行测序分析。 结果 发现ACTN4基因新错义突变L316P，该家系患病成员起病年龄平均（38.7±7.4）岁，肾功能损害进展相对缓慢，家系3例患病成员均为突变杂合子。发现TRPC6基因新杂合错义突变Q889K，该家系患者起病年龄平均（38.0±4.2）岁，肾功能损害进展也较缓慢，家系中临床表现存在个体差异，家系中3例患病成员均为突变杂合子。发现TRPC6静止突变G467G。所有家系中未发现NPHS2致病突变。健康对照组200条染色体亦未发现以上突变。 结论 在31例迟发性FSGS家系中发现2个家系携带致病相关突变：ACTN4新突变L316P和TRPC6新突变Q889K。在中国人群家族性迟发性FSGS中，ACTN4及TRPC6基因突变是致病原因之一，尚未发现NPHS2相关致病突变。     

Primary focal segmental glomerular sclerosis in children: clinical course and prognosis

To review the clinical course and identify prognostic factors, we retrospectively analyzed 92 children with steroid-resistant primary focal segmental glomerulosclerosis (FSGS). The mean age of onset was 80.4+/-42.4 months. The mean follow-up duration was 98.2+/-63.3 months. Eighty-five patients presented with nephrotic syndrome and seven presented with asymptomatic proteinuria. Thirty-three patients were initial responders to steroid treatment (late non-responders) and 59 were initial nonresponders. At last follow-up, 36 patients (39.1%) were in complete remission, and 29 (31.5%) progressed to chronic renal failure (CRF). Renal survival rates at 5, 10, and 15 years were 84, 64, and 53%, respectively. By morphological classification, there were tip variants (6.1%), collapsing variants (10.6%), cellular variants (1.5%), perihilar variants (9.1%), and NOS (not otherwise specified, 72.7%). Among the variants, there were no significant differences in age of onset, degree of proteinuria, response to treatment, or progression to CRF. Poor prognostic factors for CRF included: asymptomatic proteinuria at presentation, initial renal insufficiency, higher segmental sclerosis (%), severe tubulointerstitial change, initial nonresponse, and absence of remission. In the multivariate analysis, an increase in the initial serum creatinine and resistance to treatment were independent risk factors for CRF. A more prolonged use of corticosteroid therapy and early introduction of cyclosporin A (CsA) may improve the prognosis for primary FSGS in patients with initial steroid nonresponsiveness.     

Role of C3a and C5a in focal segmental glomerulosclerosis

Objective To study the role of C3a and C5a in focal segmental glomerulosclerosis (FSGS) patients. Methods (1) A total of 66 patients with FSGS confirmed by renal biopsy were selected, including 18 cases of tip lesion, 11 cases of perihilar, 22 cases of not otherwise specified (NOS), 10 cases of cellular, and 5 cases of collapsing FSGS. The normal renal tissue resected from patients with kidney tumor was taken as a negative control. The expression of C3a and C5a in renal tissues was detected by immunohistochemistry. (2) Serum and urine samples from these 66 FSGS patients were collected, and serum and urine samples from 10 healthy adult selected from the same physical examination center in the same term were used as normal controls. The levels of C3a and C5a in serum and urine were detected by enzyme-linked immunosorbent assay (ELISA). Results (1) Immunohistochemical results showed that C3a and C5a were deposited in glomerulus of FSGS patients, and no deposition in normal renal tissues. The semi-quantitative score showed that kidney C3a score was significantly correlated with serum creatinine (r=0.547, P＜0.001) and 24 h urine protein (r=0.329, P=0.007) in FSGS patients, and kidney C5a score was also significantly correlated with serum creatinine (r=0.415, P＜0.001) and 24 h urine protein (r=0.414, P＜0.001) in FSGS patients. (2) The levels of serum C3a and C5a in FSGS patients were higher than those in healthy adults (both P＜0.05), but there was no significant difference among the five pathological types (P＞0.05). The levels of urinary C3a/urinary creatinine, urinary C5a/urinary creatinine were higher in FSGS patients than those in healthy adults (all P＜0.05). The levels of urine C3a/urinary creatinine and urinary C5a/urinary creatinine in collapsing FSGS were higher than other FSGS types (all P＜0.01), but there was no significant difference among the tip lesion, the perihilar, the not otherwise specified and the cellular (P＞0.05). (3) Urinary C3a/urinary creatinine levels were significantly correlated with serum creatinine (r=0.774, P＜0.001) and 24 h urine protein (r=0.430, P＜0.001) in FSGS patients, and urinary C5a/urinary creatinine levels were also significantly correlated with serum creatinine (r=0.677, P＜0.001) and 24 h urine protein (r=0.333, P=0.007) in FSGS patients. Conclusion Complement C3a and C5a may be involved in the pathogenesis of FSGS and may be related to the severity of FSGS.     

Clinico-pathological characterization and outcome of primary focal segmental glomerular sclerosis with deposition of IgM

Objective To explore the clinico-pathological features and outcomes of primary focal segmental glomerular sclerosis with IgM deposition. Methods One hundred and two patients with primary focal segmental glomerular sclerosis (pFSGS) in Hangzhou hospital of traditional Chinese medicine between 1996 and 2012 were retrospectively studied. The patients were divided into IgM deposition group (n=66) with IgM deposition in glomeruli and none-IgM deposition group (n=36)without IgM deposition. Baseline and clinical characteristics of all FSGS patients were assessed and outcomes were reviewed. The survival rates of the patients were analyzed using theKaplan-Meiermethod. Results (1) There were not difference in age, sex ratio, incidence of microscopic hematuria, hypertension, renal insufficiency, eGFR, Ccr and Scr between two groups. However, proteinuria, incidence of nephrotic syndrome, urine microalbumin, urine NAG, serum cholesterol, serum high-density lipoprotein, and serum IgM in IgM deposition group were significantly higher than those in none-IgM deposition group (P＜0.05), serum albumin and serum IgA in IgM deposition group were significantly lower than those in none-IgM deposition group (P＜0.05). (2) The IgM deposition group had a significantly higher incidence of glomerular deposition of IgA, IgG, C3, C1q and fibrinogen than none-IgM deposition group (P＜0.05). The score of mesangial matrix proliferation in the IgM deposition group was lower than that in none-IgM deposition group (P＜0.05). (3) fifty-four patients (35 patients in IgM deposition group and 19 patients in none-IgM deposition group） were followed-up for a median of 64.6 (22.8, 103.8) months. Progression to renal failure was observed in 5 patients of IgM deposition group and none in none-IgM deposition group. Compared with the none-IgM deposition, the survival rates in the IgM deposition group were statistically lower (P＜0.05).Conclusions PFSGS patients with IgM deposition were severer in proteinuria, higher incidence ofIgA, IgG, C3, C1q and fibrinogen deposition in glomeruli and worse outcome than those without IgM deposition.     

Clinical and pathological features of idiopathic membranous nephropathy with focal segmental lesion

Objective To investigate the clinical-pathological features and prognosis of idiopathic membranous nephropathy (IMN) with focal segmental lesion. Methods Two hundred and ninety-eight patients with biopsy-proven IMN in our hospital were retrospectively analyzed. The patients were divided into three groups: without focal segmental lesion group (FSL-), with focal segmental glomerulosclerosis group (FSGS) and with early focal segmental lesion group (EFSL). The differences of clinical and pathological features and prognosis in the 3 groups were studied. Results There were later pathological stage, higher ratio of chronic renal tubulointerstitial damage and global glomerular sclerosis in FSGS group than those in the other two groups (all P＜0.05). The male ratio in EFSL group was higher than that inFSL- group (P＜0.01), while the level of serum albumin was lower (P＜0.05). Compared withFSL- group, there was longer average course before renal biopsy, higher blood pressure and levels of Scr in FSGS group (all P＜0.05)．Furthermore, the remission rate in EFSL group was lower than that in FSGS group andFSL- group. Survival analysis showed that FSGS group had worse prognosis (FSGS toFSL-, P=0.005, FSGS to EFSL, P=0.008). The analysis of risk factors suggested that triacylglycerol (OR=1.519, P=0.017), glomerulosclerosis (OR=1.073, P=0.041) and FSGS lesion (OR=5.960, P=0.009) were independent risk factors for renal death. Conclusions There were some differences between EFSL and FSGS lesion, both in clinical manifestations and pathology. FSGS lesion was independent predictive factor for progression to renal death. And the lowest remission rate was in EFSL group.     

原发性局灶节段性肾小球硬化ACTN4和SYNPO基因启动子的突变

目的 探讨散发性原发性局灶节段性肾小球硬化（FSGS）患者中ACTN4和SYNPO基因启动子区突变的致病作用。 方法 盐析法提取82例FSGS患者外周血基因组DNA,经引物设计及PCR扩增后测序。突变位点经转录因子结合模拟软件筛选,pGL3-Basic构建表达载体与pRL-SV40质粒瞬时共转染PC12细胞,双荧光素酶法检测基因表达。检测患者父母头发DNA。免疫荧光检测患者肾组织?琢-actinin-4和synaptopodin蛋白表达。 结果 3例ACTN4基因突变分别为1－34C>T、1－590delA和（1－1044delT）+（1－797T>C）+（1－769A>G）。2例SYNPO基因突变分别为1－24G>A和1－851C>T。1例患者分别接受父母1－1044delT和 1－797T>C变异。除1－1044delT组外,变异组荧光素酶表达强度比正常组有不同程度下降,与突变患者肾组织?琢-actinin-4和synaptopodin免疫荧光强度下降基本相符。 结论 ACTN4和SYNPO基因启动子区顺式作用元件区的变异影响基因的转录,可能在散发性FSGS发病中起作用。     

The effect of proteinase inhibitors on glomerular albumin permeability induced in vitro by serum from patients with idiopathic focal segmental glomerulosclerosis.

BACKGROUND: The putative circulating factor responsible for the glomerular permeability alterations induced in vitro by serum from patients affected by focal segmental glomerulosclerosis (FSGS) remains unidentified. We have observed that a serine proteinase isolated from patient serum increases albumin permeability in isolated glomeruli. The objective of the present study was to determine the effect of various proteinase inhibitors on glomerular albumin permeability (P(alb)) in isolated glomeruli incubated with FSGS serum. METHODS: The study population consisted of 12 FSGS patients (eight males; mean age: 21+/-10 years) previously shown to have elevated serum albumin permeability activity. P(alb) was determined by measuring the change in glomerular volume induced by applying oncotic gradients to isolated healthy rat glomeruli treated with patient serum in comparison to control serum. Solutions of seven different proteinase inhibitors (0.5 mg/ml) were added to the incubation media with the sera (1:1 vol/vol): serine proteinase inhibitors (PMSF, leupeptin, aprotinin, gabexate mesylate), the cysteine proteinase inhibitor E-64, the metalloproteinase inhibitor EDTA and the aspartate proteinase inhibitor pepstatin. Sera from the same patients were also tested with the addition to the incubation media of quinaprilat, an inhibitor of the metalloproteinase angiotensin-converting enzyme. RESULTS: Mean P(alb) of the sera was 0.86+/-0.11, with the addition of PMSF 0.41+/-0.09, leupeptin 0.30+/-0.17, aprotinin 0.09+/-0.14, gabexate mesylate 0.27+/-0.25, E-64 0.81+/-0.09, EDTA 0.68+/-0.10 or pepstatin 0.76+/-0.11. The mean P(alb) of the sera combined with quinaprilat was reduced to 0.34+/-0.35. Thus, only the serine proteinase inhibitors consistently blocked the increased P(alb) induced by the FSGS sera. CONCLUSIONS: In the cascade of events that lead to the initiation of glomerular fibrosis in FSGS, the putative glomerular permeability factor associated with FSGS may require a serine proteinase to effect its activity.     

Treatment of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) commonly presents with nephrotic syndrome (NS), and spontaneous remission is rare. NS is a poor prognostic marker for renal survival, and has serious extra-renal complications. Rapid remission using drugs with minimal side effects is desirable. Tacrolimus (Tac) has a more potent immunosuppressive effect and may be less toxic at therapeutic doses than ciclosporin (CsA). Although CsA has a role in the treatment of FSGS, there are limited data regarding the use of Tac monotherapy in this setting, and this is limited to experience in children. METHODS: We prospectively report the outcome for six adult patients with FSGS treated with Tac from first presentation with NS, and for a further five adult patients in remission on CsA converted to Tac in an attempt to arrest a progressive decline in renal function on CsA. RESULTS: All six patients treated with Tac from presentation with NS achieved remission after 6.5 +/- 5.9 months. The serum albumin for the group increased from 26.8 +/- 4.6 to 37.7 +/- 1.9 g/l (P = 0.003), and there was a significant reduction in the mean 24 h urinary protein excretion from 11.0 +/- 4.5 to 2.8 +/- 2.5 g (P = 0.003). All remissions were partial with a mean reduction in 24 h urinary protein of 75.2 +/- 16.8%. There was a non-significant reduction in MDRD GFR from 71.7 +/- 22.4 to 55.9 +/- 9.7 ml/min/1.73 m(2) (P = 0.07), which manifest within the first 3 months of Tac treatment but renal function was subsequently stable. The mean follow-up for the group was 12.8+/-5.5 months. Two of the five patients converted from CsA to Tac maintained complete remission, and the remaining three patients in partial remission had further reductions in proteinuria. There was an improvement in renal function concomitant with conversion to Tac in each case, with an overall improvement in MDRD GFR for the group of +1.9+/-1.1 ml/min/1.73 m(2)/month. CONCLUSIONS: Tac rapidly and effectively induced remission of NS in FSGS. Conversion from CsA to Tac indicates that Tac might be a more potent agent with less nephrotoxicity in this setting.     

Development of focal segmental sclerosis and hyalinosis in hemolytic uremic syndrome

Renal biopsies from 19 boys and 11 girls, most with moderate or severe forms of hemolytic uremic syndrome (HUS) of the classic diarrhea-associated type, were analyzed as part of their long-term follow-up. Patients were biopsied because of late or persistent proteinuria, hypertension, and prolonged renal failure. The median length of follow-up was 11.2 years (range 0.9 – 22.0 years). Four histological groups were identified: focal segmental glomerulosclerosis and hyalinosis (FSGSH) (17 patients), diffuse mesangial proliferative glomerulonephritis (DMPGN) (9 patients), diffuse glomerulosclerosis (2 patients), and minimal glomerular changes (2 patients). The median interval between the onset of disease and renal biopsy was significantly shorter in DMPGN than in FSGSH (P <0.001). The pathological findings may be the expression of two different stages of the same dynamic process: a regular sequence of glomerular lesions consisting of early DMPGN, followed by FSGSH. This lesion would ultimately lead to the final stage of global glomerulosclerosis. At the last examination, only a quarter of the patients had normal renal function. These observations also confirm that prolonged oligoanuria during the acute stage of HUS frequently results in an unfavorable long-term prognosis. Received December 16, 1994; received in revised form and accepted February 12, 1996     

Abrogation of nephrotic proteinuria by rituximab treatment in a renal transplant patient with relapsed focal segmental glomerulosclerosis

Relapse of focal segmental glomerulosclerosis (FSGS) after renal transplantation is 20-40%. Recurrence after a first relapse is 80%. The only current treatment is plasmapheresis and/or cyclophosphamide. We report successful treatment of a second relapse in a 48-year-old patient. At age 33, FSGS was diagnosed. The patient began hemodialysis 1 year later. In her first renal transplant, she developed recurrent FSGS and reached terminal transplant failure 3 years later. Eight years later, a second transplant was performed. Immunosuppressive regimen: steroids, mycophenolate mofetil (MMF), tacrolimus (TAC), and rabbit anti-thymocyte globulin. Proteinuria of 2-6 g/day was detected and a biopsy showed recurrent FSGS. Plasmapheresis was started without success. Another biopsy still showed FSGS. The patient received two doses of rituximab (375 mg/m2 each) i.v. Three weeks later, proteinuria was 350 mg/day (serum-creatinine 1.6 mg/dl). Twelve months later, proteinuria was at 90 mg/day. Rituximab might be an option for recurrent FSGS after renal transplantation.