Effect of immunoadsorption on refractory idiopathic focal and segmental glomerulosclerosis

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.     

Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS)

Background. Steroid-resistant nephrotic syndromes (NS) withfocal and segmental glomerulosclerosis (FSGS) can be differentiatedinto sporadic and syndromic forms. In sporadic NS, a circulatingFSGS-factor is discussed in the pathogenesis and is thoughtto inhibit the synthesis of nitric oxide (NO) from L-arginineby blocking the NO synthase (NOS). Asymmetric dimethylarginine(ADMA) is an endogenous inhibitor of all types of NOS. In aprevious study we did not find an elevation of ADMA in a syndromicform of FSGS, the Schimke-immuno-osseous dysplasia. Here wereport for the first time data on the L-arginine/NO pathwayin sporadic FSGS of childhood. Methods. Nine children (5 to 18 years of age) suffering fromsporadic FSGS and age-matched healthy controls were investigated.ADMA in plasma and urine as well as L-arginine in plasma weredetermined by gas chromatography–tandem mass spectrometry.The NO metabolites nitrate and nitrite were measured in plasmaand urine by gas chromatography–mass spectrometry (GC-MS).The ADMA metabolite dimethylamine (DMA) was measured in urineby GC-MS. Results. We found elevated plasma levels of ADMA in childrensuffering from sporadic FSGS compared to healthy controls (851nmol/L versus 684 nmol/L, P = 0.008). An inverse correlationbetween ADMA and glomerular filtration rate (GFR) was foundin sporadic FSGS (Pearson's correlation coefficient –0.784,P = 0.012). Conclusion. Our study suggests that ADMA synthesis is elevatedin sporadic FSGS. This finding argues for the involvement ofADMA in the pathogenesis of this disease in childhood.     

家族性局灶节段性肾小球硬化3家系临床表型与相关基因连锁分析

目的 分析3个家族性局灶节段性肾小球硬化（FFSGS）家系的临床表型,并通过连锁分析方法进行已知基因的排除性定位研究。 方法 对3个家系中的所有患者进行临床检查。应用等位基因共享分析和两点连锁分析的方法，在已知的FFSGS 相关基因NPHS1、NPHS2、ACTN4、TRPC6、CD2AP和WT1基因的所在染色体区域，选取14个微卫星标记进行连锁分析研究。结果 3个FFSGS家系的遗传方式均为常染色体显性遗传，54名家系成员中有16例患者，其临床表型不同，2个家系的起病年龄相对较大，在青少年期发病，而家系A中有2个患者发病年龄偏小，最小者1岁发病，而家系中其他患者都是在25岁以后发病。3个家系中有4例因尿毒症病故，另2例尿毒症行肾移植治疗，还有2例出现肾功能不全。其中家系A的先证者14岁即出现了肌酐增高。应用D19S191、D19S220、D19S224、D1S215、D1S416、D1S466、D11S1391、D11S1986、D11S2000等微卫星标记（STR）对家系A进行NPHS1、NPHS2、ACTN4和TRPC6基因的两点连锁分析，测得各个标记位点在重组率θ= 0 时，最大的LOD 值为0.18（D11S1391）；在θ= 0.1 时，最大的LOD 值也为0.18（D11S1986）；在θ= 0.2 时，得到本组最大的LOD 值也只为0.47（D19S220），均不支持连锁。提示家系A与所检测的9个微卫星DNA 标记位点无共分离。用上述微卫星标记以及ACTN4基因内的微卫星标记D19S422、CD2AP基因所在位点的微卫星标记D6S936和D6S1566、WT1基因所在位点的微卫星标记D11S2370对家系A进行等位基因共享分析，结果该家系致病基因与ACTN4、NPHS1、NPHS2、TRPC6、CD2AP和 WT1等基因所在位点不连锁。应用D19S191、D19S220、D19S224、D19S422、D1S215、D1S416、D1S466、D11S1391、D11S1986、D11S2000、D6S936和D6S1566等微卫星标记（STR）对家系B和C进行等位基因共享分析，结果这2个家系的致病基因与ACTN4、NPHS1、NPHS2、 TRPC6和CD2AP等基因所在位点均不连锁。结论 3个中国人常染色体显性FFSGS家系，具有明显的临床异质性。已知基因NPHS1、NPHS2、ACTN4、TRPC6、CD2AP和WT1不是家系A的致病基因；NPHS1、NPHS2、ACTN4、TRPC6和CD2AP不是家系B和C的致病基因。     

NPHS2 Mutations in Steroid‐Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum

Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal‐recessive form of nonsyndromic steroid‐resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid‐resistant nephrotic syndrome before the age of 6 years and rapidly progress to end‐stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype–phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database ( www.lovd.nl/NPHS2 ) software that will allow the inclusion of future reports.     

高脂饲料对肾病大鼠高脂血症和肾小球硬化的影响

以高脂饲料喂养阿霉素肾病大鼠观察高脂饲料对肾病大鼠内源性高脂血症和肾小球硬化的病理改变的影响。结果表明：高脂饲料能显著升高血清总胆固醇（ＴＣ）及低密度脂蛋白胆固醇（ＬＤＬ－Ｃ），致使尿蛋白排泄量增加，肾小球内脂质沉积加重，“泡沫”细胞增多，局灶性节段性肾小球硬化（ＦＳＧＳ）范围扩大。提示高脂血症在肾小球损害发展过程中加剧对肾脏病理的恶化．     

前列腺素E1对局灶节段性肾小球硬化模型大鼠肾血管内皮生长因子表达的影响

目的：探讨前列腺素E1脂微球载体制剂（Lipo-PGE1）,地塞米松对局灶节段性肾小球硬化模型大鼠的影响.方法：用单侧肾切除加1周后静脉注射多柔比星（5 mg/kg）的方法建立局灶节段性肾小球硬化（FSGS）大鼠模型,设立假手术组为正常对照组,同时设立FSGS模型组、地塞米松治疗组、Lipo-PGE1治疗组、 Lipo-PGE1联合地塞米松治疗组.检测各组术后第2,6,10周末的尿蛋白及第10周末血清尿素氮、肌酐、总蛋白、白蛋白及肾组织病理改变,并应用免疫组化方法检测肾组织内胶原Ⅰ（Col Ⅰ）、胶原Ⅲ（Col Ⅲ）的沉积和血管内皮生长因子（VEGF）蛋白质的表达.结果：Lipo-PGE1治疗组比FSGS模型组尿蛋白排泄量明显减少,血肌酐、尿素氮水平下降,肾小球增生、硬化程度及肾小管间质病变程度明显减轻（P〈0.01）;免疫组化显示,模型组肾组织胶原Ⅰ、胶原Ⅲ沉积增多,VEGF蛋白表达减少, Lipo-PGE1治疗组比模型组减少（P〈0.01）, 地塞米松治疗组比模型组尿蛋白排泄量增加,血肌酐、尿素氮水平上升,肾小球增生、硬化程度及肾小管间质病变程度加重, Lipo-PGE1联合地塞米松治疗组表现与地塞米松治疗组无显著差异（P〉0.05）.结论： Lipo-PGE1对局灶节段性肾小球硬化模型大鼠肾脏损害有一定的保护作用,可能与影响肾小球足细胞VEGF表达有关,但是不能纠正由于地塞米松导致的FSGS模型加重的表现.     

Rituximab treatment for posttransplant lymphoproliferative disorder (PTLD) induces complete remission of recurrent nephrotic syndrome

A 12-year-old Japanese boy who underwent kidney transplantation with a kidney from his mother developed severe proteinuria immediately after the operation. Because his original disease was nephrotic syndrome (focal segmental glomerulosclerosis, or FSGS) and electron microscopic examination of the renal biopsy showed foot process fusion, we diagnosed this as a recurrence of nephrotic syndrome to the transplanted kidney. Four months after the transplantation, posttransplant lymphoproliferative disorder (PTLD) developed, which was pathologically diagnosed as diffuse large B cell lymphoma. Treatment consisting of a reduction in immunosuppression resulted in improvement in PTLD a month after the start of treatment. However, relapse occurred 2 months after the first onset of PTLD, which we treated with rituximab (CD-20 monoclonal antibody 375 mg/m²) once weekly for a total of four doses. The PTLD resolved immediately after the rituximab treatment was started, and, interestingly, urinary protein levels also improved at the same time. Three years later, the boy shows no signs of PTLD, and no proteinuria has been detected. These findings suggest that rituximab may be an effective treatment for recurrence of nephrotic syndrome after transplantation and that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation.     

Preventing recurrence of focal segmental glomerulosclerosis following renal transplantation: a case report

While the recurrence of FSGS in a primary renal transplant has been well studied, strategies to prevent subsequent recurrence in later transplants, has not been well formulated. This is important considering that one center's experience with adults reported an initial recurrence rate of 57% with reoccurrence of 37% in subsequent transplants. However, renal function was maintained in 62% (1). In pediatrics, data from a single-center reported 100% recurrence of FSGS in the second allograft after an initial recurrence of 52% (2). Two commentaries reviewing such data, one each in adults and pediatrics, suggested that the benefits of living-related donation might not be realized in patients with FSGS because of this frequent recurrence (3, 4). Here, we report a patient who was considered to be at very high risk for post-transplant recurrence of FSGS, because of the established risk factors, who was successfully retransplanted after a course of pretransplant plasmapheresis, followed by post-transplant plasmapheresis and the use of cyclosporine. Eighteen months post-transplant, he has no proteinuria and his serum creatinine is 1.2 mg/dL.     

Evaluation of MicroRNAs miR-196a,miR-30a-5P,and miR-490 as Biomarkers of Disease Activity among Patients with FSGS

Background and objectives

This study aimed to identify urinary microRNAs (miRNAs) as biomarkers for FSGS disease activity.

Design, setting, participants, & measurements

Candidate urinary miRNAs were identified in pooled urine samples from patients with active FSGS (FSGS-A) and FSGS in remission (FSGS-CR), and were then validated using individual samples. Their levels were compared both under different treatment responses in a prospective study of FSGS and in patients with different membranous nephropathy (MN) and diabetic nephropathy (DN) disease activity. The prediction of these miRNAs for treatment responses was further analyzed in both retrospective and prospective cohorts of patients with FSGS.

Results

All 54 miRNAs were included as candidate biomarkers, including those with high levels in patients with FSGS-A (n=9) under the TaqMan Low Density Array as well as those with conserved expression in kidneys and involved in immune response. TaqMan probe-based quantitative RT-PCR confirmed the higher levels of four miRNAs in patients with FSGS-A in two independent cohorts (n=18 and n=80). Urinary miR-196a, miR-30a-5p, and miR-490 discriminated FSGS-A from FSGS-CR, with an area under the curve of ≥0.80. After steroid treatment, their levels were lower in steroid-responsive patients with FSGS (all P<0.001), but were unchanged in steroid-resistant patients. The levels of miRNAs were similar between active MN and MN in remission as well as active DN and incipient DN (all P>0.05). Urinary miR-30a-5p marginally predicted the response to steroid treatment in patients with FSGS-A, with an area under the curve of 0.63 (P=0.03).

Conclusions

The levels of urinary miR-196a, miR-30a-5p, and miR-490 are associated with FSGS disease activity.