Long-term response to peginterferon in hepatitis C virus-associated nephrotic syndrome from focal segmental glomerulosclerosis

Abstract

Hepatitis C virus (HCV) infection is a global public health problem. Chronic HCV infection is an important cause of chronic liver disease. Since the first reported association between HCV and membranoproliferative glomerulonephritis (MPGN) in 1993, HCV has been described with other types of glomerular diseases, although less frequently. Focal segmental glomerulosclerosis (FSGS) is one such glomerular disease that has been rarely reported in association with HCV. Antiviral therapy with interferon and ribavirin has been shown to be beneficial in HCV-associated MPGN. The optimal therapy of HCV-associated FSGS is not currently known. To our knowledge, long-term response to pegylated interferon monotherapy in treatment of HCV-associated FSGS has not been reported. We report an adult patient with HCV-associated FSGS who presented with nephrotic syndrome and renal failure. Treatment with pegylated interferon alfa-2a monotherapy resulted in sustained virological response with a clinical remission of nephrotic syndrome and stabilization of renal function. Patient continued to remain in clinical remission of nephrotic syndrome with stable renal function, 5 years after treatment. We also briefly review the literature on HCV-associated glomerular diseases, particularly HCV-associated FSGS.     

Active proteases in nephrotic plasma lead to a podocin‐dependent phosphorylation of VASP in podocytes via protease activated receptor‐1

Focal segmental glomerulosclerosis (FSGS) is associated with glomerular podocyte injury. Podocytes undergo dramatic changes in their actin structure, with little mechanistic insight to date into the human disease. Post‐transplantation recurrence of FSGS is the archetypal form of the disease caused by unknown circulating plasma ‘factors’. There is increasing indication that plasma protease activity could be central to this disease. Using clinical plasma exchange material, collected from patients in relapse and remission stages of disease, the effects of FSGS plasma on human conditionally immortalized podocytes (ciPods) were studied. We show that vasodilator stimulated phosphoprotein (VASP) is phosphorylated in response to relapse plasma from ten consecutively tested patients, and not in response to paired remission plasma or non‐FSGS controls. The phosphorylation signal is absent in human podocytes carrying a pathological podocin mutation. To test for a plasma ligand, inhibition of proteases in relapse plasma leads to the loss of VASP phosphorylation. By the use of siRNA technology, we show that proteases in the plasma signal predominantly via protease activated receptor‐1 (PAR1) to VASP. Mechanistically, FSGS plasma increases podocyte motility, which is dependent on VASP phosphorylation. These data suggest a specific biomarker for disease activity, as well as revealing a novel and highly specific receptor‐mediated signalling pathway to the actin cytoskeleton. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

霉酚酸酯对局灶节段性肾小球硬化(FSGS)治疗作用的研究

目的:用霉酚酸酯(MMF)对以阿霉素肾病大鼠建立的局灶节段性肾小球硬化(FSGS)模型,进行干预,检测结缔组织生长因子(CTGF)的表达,研究霉酚酸酯对FSGS的治疗作用,并探讨作用机理。方法:SD大鼠18只,分为对照组、阿霉素肾病组、MMF治疗组(每组大鼠6只)。肾病组、治疗组大鼠尾静脉一次性注入阿霉素7.5mg/kg,对照组大鼠尾静脉注入等量生理盐水。治疗组于第6周起MMF 20mg.kg-1.d-1混悬于1mL蒸馏水灌胃,其他组等量蒸馏水灌胃。第10周处死所有大鼠,观察肾组织病理变化,并以免疫组织化学、Western blot方法检测肾组织CTGF蛋白水平。结果:阿霉素肾病组大鼠较对照组大鼠肾小球系膜及基质明显增生,免疫组织化学染色及western blot显示肾小球和肾小管区CTGF蛋白表达明显上升(P<0.05),霉酚酸酯治疗组肾小球系膜和基质增生较肾病组明显减轻,肾小球和肾小管区CTGF蛋白表达明显低于肾病组(P<0.05)。结论:霉酚酸酯可以减轻肾脏间质纤维化病变,机理与抑制CTGF的表达有关。     

Nephrotic Syndrome: Components,Connections, and Angiopoietin-Like 4–Related Therapeutics

Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), and lipiduria. Each component has been investigated individually over the past four decades with some success. Studies published recently have started unraveling the molecular basis of proteinuria and its relationship with other components. We now have improved understanding of the threshold for nephrotic-range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing key amino acids in its sequence can be used successfully to treat proteinuria. Treatment strategies on the basis of fundamental relationships among different components of nephrotic syndrome use naturally occurring pathways and have great potential for future development into clinically relevant therapeutic agents.     

FSGS患者地塞米松冲击治疗前后的尿液差异蛋白图谱及意义

目的:采用双向凝胶电泳技术(2-DE),分析原发性局灶节段硬化性肾小球肾炎(FSGS)患者使用地塞米松冲击治疗前后的尿液蛋白图谱的差异及其敏感性。方法:以FSGS患者为研究对象,观察地塞米松冲击治疗前、冲击治疗后3d、冲击治疗后2周3个时间点的尿液双向电泳图谱的蛋白点差异分布,并与其同期尿液分析及24h尿蛋白定量结果相比较。结果:FSGS患者尿液样品2-DE图谱显示:地塞米松冲击治疗前与冲击后3d比较其蛋白点数量存在明显差异,但24h蛋白定量值差异无统计学意义(P>0.05);地塞米松冲击治疗前与冲击后2周比较其蛋白点数量存在明显差异且24h蛋白定量值差异有统计学意义(P<0.05)。结论:FSGS患者使用地塞米松冲击治疗后,其尿液中的蛋白点明显减少,结合其24h尿蛋白定量结果提示:尿蛋白点数减少与临床疗效具有一致性,其敏感程度较24h尿蛋白定量高。     

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.     

Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy.

BACKGROUND: The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. METHODS: We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. RESULTS: We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). CONCLUSION: FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.