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.     

Intensive and Prolonged Treatment of Focal and Segmental Glomerulosclerosis Recurrence in Adult Kidney Transplant Recipients: A Pilot Study

No treatment has consistently induced long-term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an open-label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18-month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high-dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 ± 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05–0.3 g/day) and 0.19 g/day (range 0.05–1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE-dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.     

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。     

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。     

A case of crescentic glomerulonephritis in a patient with COVID-19 infection: A case report and literature review

Rationale:Kidney involvement with COVID-19 infection is a well-known complication, and the majority of kidney involvement is related to ischemic injury/acute tubular injury. However, there are some cases of glomerulonephritis, the etiology of which is not yet known, but an immune process is likely to be the trigger.Patient concerns:A 27-year-old man presented to our hospital with facial puffiness and lower-limb swelling.Diagnosis:Laboratory assessment revealed features of impaired kidney function with proteinuria and hematuria; COVID-19 polymerase chain reaction was positive, which was consistent with pauci-immune crescentic focal segmental glomerulonephritis.Intervention:After renal biopsy, the patient was started on methylprednisolone and rituximab. Due to worsening kidney parameters, he underwent intermittent hemodialysis as needed.Outcome:Kidney function tests partially improved; he was discharged on oral steroids with follow-up in the nephrology clinic to observe for the need for further hemodialysis.Lessons:We conducted a literature review of cases of glomerulonephritis associated with COVID-19 and described numerous types of glomerulonephritis. This report highlights the importance of recognizing emerging glomerulonephritis with COVID-19, the different pathological patterns of renal biopsies, and management interventions and responses.     

Focal and segmental glomerulosclerosis: multiple pathways are involved

Focal segmental glomerulosclerosis (FSGS) is not a disease but a clinicopathologic entity. The term FSGS itself is a misnomer because its lesions are not always focal, segmental, or sclerotic. Its clinical expression also widely varies and is nonspecific. Confronted with such diversity, one cannot but translate the title of this contribution into a unifying version focusing on the podocyte, initial culprit, or victim of multiple processes leading to FSGS. Some have been identified in human glomerulopathies and/or in animal or cell culture models, and are classified as secondary. Genetic forms, nonsyndromic or syndromic, have adduced a wealth of knowledge on the slit diaphragm architecture and explain the reason for their steroid resistance. Others, mostly expressed by a nephrotic syndrome, will be considered as idiopathic until the offending factor(s) that affect the molecular array of the slit diaphragm filtration barrier are identified and counteracted. Recent research has lead to suggesting that FSGS is not a T-cell–driven autoimmune glomerulopathy. Thus, treatments considered as etiologic, including glucocorticoids and calcineurin inhibitors, are in fact endowed with a mode of action on podocytes that suggests that drugs used such as immunosuppressors also might be considered as antiproteinuric agents.     

Second-line options for refractory steroid-sensitive and -resistant nephrotic syndrome

Although initially, many children with idiopathic nephrotic syndrome respond to steroid therapy, a repeated course for patients with relapses often causes significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, and so far, cyclophosphamide or levamisole have been regarded as first-choice options, although the latter is no longer available in many countries. Data are accumulating that mycophenolic acid may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and are often used after cytotoxic treatment, but long-term treatment is necessary, raising concerns regarding the accumulation of side effects. Still, some patients show a tendency to relapse even on this maintenance regimen and some even have a refractory course that creates a medical dilemma. For this situation, recent data have demonstrated an effect of monoclonal antibodies directed to B cells – rituximab, a drug that may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to initial steroid treatment need genetic testing and a renal biopsy, since focal segmental glomerulosclerosis may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors (mainly cyclosporine but also, recently, tacrolimus). Cyctotoxic treatment, especially intravenous cyclophosphamide, has been found to be effective in steroid-resistant nephrotic syndrome by some studies but is inferior to calcineurin inhibitors. In addition, mycophenolic acid and rituximab have been used in children with primary focal segmental glomerulosclerosis; however, response seems to be inferior in comparison with patients with steroid-sensitive nephrotic syndrome. Taken together, idiopathic nephrotic syndrome, including steroid-sensitive as well as steroid-resistant patients, is a potentially serious disorder. Although much progress has been made in recent years and a wide arsenal of immunological interventions is available, some patients have a treatment refractory course. Prospective studies or at least standardization of treatment for complicated cases is urgently needed.     

277例肾病患者足细胞相关分析

目的 分析肾脏疾病患者不同类型的病理改变与足细胞数量的关系,研究二者之间的相关性,寻找足细胞在判断疗效与预后方面的积极意义.方法 对277例肾穿病人肾组织进行常规病理染色及免疫荧光、电镜检查进行病理分型,同时进行肾脏足细胞计数,对二者进行相关性分析,了解肾小球足细胞数量与肾脏病病理分型及预后是否相关.结果 局灶节段性肾小球肾炎(FSGS)、膜性肾病(MN)与搪尿病肾病(DN)和足细胞病变有绝对关系:肾小球足细胞数目与尿蛋白多少呈负相关;尿蛋白是临床判断肾脏病活动与否的依据之一.结论 故肾小球足细胞可以作为判断临床肾病活动的依据之一.