Investigational drugs in development for focal segmental glomerulosclerosis

Introduction: Focal segmental glomerulosclerosis is an important cause of end stage kidney disease and is a paradigm for the study of glomerular scarring. There are no FDA approved treatments for this condition. Current therapies, assessed based on reduction in proteinuria, are generally effective in a subset of patients which suggests that FSGS is a heterogeneous group of glomerular disorders or podocytopathies that converge on a common histopathological phenotype.

Areas covered: We searched for investigational drugs agents that target different pathophysiological pathways using the key words ‘FSGS’ and ‘podocyte’ in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Medline, the Web of Science and the Cochrane Central Register of Controlled Trials Library.

Expert opinion: Progress is being made in defining the mechanism of action of subtypes of FSGS. Current and investigational therapies for FSGS target these different pathways of injury. It is anticipated that advances in systems biology will further refine the classification of FSGS by subdividing the disease based on the primary mechanism of glomerular injury, identify biomarkers to discriminate between different subtypes, and enable appropriate selection of appropriate therapy for each individual in accordance with the goals of precision medicine.     

局灶节段性肾小球硬化之微观辨证

中医药在防治慢性肾脏病的实践中将微观辨证引入中医的辨证论治,开展了一些临床与基础研究。现代医学的实验检查、肾组织活检提供的病理诊断,极度丰富和延伸了中医传统辨证的依据,整体观念指导下的微观辨证已得到众多医家的认同。局灶节段性肾小球硬化(Focal segmental glomerulus sclerosis,FSGS)之中医微观辨证,根据局灶节段性肾小球硬化患者个体化特征施治,控制疾病进展的主要病理因素,力求为难治性肾病的防治提供优质方案,从多层次、多角度认识了中医肾病"证"的本质及病理基础,探索了肾脏病的共性及其变化的普遍规律,在一定程度上提高了中医药治疗慢性肾脏病疗效评价的客观性和科学性。     

肾小球微小病变与局灶节段性肾小球硬化症足细胞中线粒体形态的定量研究(英文)

目的探索肾小球微小病变(MCD)与局灶节段性肾小球硬化症(FSGS)两种肾小球病中足细胞内线粒体的形态学差异。方法选择5例MCD和5例FSGS病例,在透射电镜放大30000倍的情况下,根据等距离曲线移动原则对每个病例拍照40张。根据Merz曲线和Gunderson测试系统选择线粒体和足细胞,测算并获得包括线粒体截面面积(A)、周长(C)、体积密度(VV)及面数密度(NA)等指标进行分析。结果 MCD和FSGS足细胞中线粒体相关参数的变异度及P值如下:A:0.47vs1.73,P=0.970;C:4.89vs24.71,P=0.590;VV:0.49vs1.74,P=0.946;NA:0.26vs0.58,P=0.602。结论 FSGS和MCD足细胞中线粒体的A、C、VV和NA等参数无统计学差异(所有P>0.05),但FSGS中所有参数的变异度均比MCD中的更明显,仍需进一步进行体视学研究。     

Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children

The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) is variable (~30%). The incidence of recurrence is less in African-Americans than in whites and Hispanics. Graft survival rates are decreased in recipients with FSGS, especially if remission of the NS is not achieved in those with recurrence. Although controversial, the use of living donor (LD) transplants are not contraindicated; however, obligatory heterozygote parental grafts with a podocin mutation should be used with caution. Optimal treatment to induce a remission post-transplant has not been delineated. Pre-transplant and/or prophylactic post-transplant pre-operative plasmapheresis (PP) for high-risk patients--especially those with recurrence in a previous graft--may be promising. An international multicenter controlled study is required to delineate the optimal approach to prevent and/or treat the recurrence of NS/FSGS.     

Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review

Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review.
Pediatr Transplantation 2010: 14: 314–325. © 2010 John Wiley & Sons A/S. Abstract: Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant management of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti‐calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS.     

X-linked Alport syndrome in Hellenic families: phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5

The X-linked Alport syndrome (ATS) is caused by mutations in COL4A5 and exhibits a widely variable expression. Usually ATS is heralded with continuous microhematuria which rapidly progresses to proteinuria, hypertension and chronic or end-stage renal disease (ESRD) by adolescence, frequently accompanied by sensorineural deafness and ocular complications. Milder forms of ATS also exist. We studied 42 patients (19M, 23F) of nine Hellenic families suspected clinically of X-linked ATS who presented with marked phenotypic heterogeneity. We identified mutations in COL4A5 in six families. Two males with nonsense mutation E228X reached ESRD by ages 14 and 18. Frameshift mutation 2946delT followed the same course with early onset renal involvement and deafness. However, two males with the milder missense mutation G624D, reached ESRD after 39 years and one patient showed thin basement membrane nephropathy (TBMN). Another 5/8 affected males with missense mutation P628L also developed ESRD between 30 and 57 years, while three exhibit only mild chronic renal failure (CRF). The data support previous findings that certain mutations are associated with milder phenotypes and confirm that mutation G624D may be expressed as TBMN with familial hematuria. Similar conclusions apply for missense mutation P628L. Interestingly, mutations G624D and P628L are near the 12th natural interruption of COL4A5 triple helical domain, which may explain the milder phenotype.     

Renal Allograft Survival in Transplant Recipients with Focal Segmental Glomerulosclerosis

Previous literature suggests that the recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is more common in recipients who have received an HLA-identical living-related (LRD) transplant. To address the question if FSGS patients can safely receive a 6-antigen match LRD kidney transplant, we analyzed death-censored renal allograft survival data of FSGS patients from the United States Renal Data System database (USRDS). Using the USRDS and the U.S. Scientific Renal Transplant Registry between the years 1988-97, we found 19259 adult primary renal transplant recipients, of which 2414 patients had FSGS as their primary diagnosis as compared to 16845 patients who had other types of glomerulonephritis (GN). A Cox proportional hazard model was used to estimate death-censored graft survival among FSGS patients with a zero mismatch LRD kidney transplant. The model included a triple interaction term comparing FSGS vs. GN vs. living donation (LD) vs. cadaveric donation (CAD) vs. zero mismatch (six antigen or HLA-identical) vs. mismatch. Annually adjusted death censored graft loss rates per 1000 patients (ADGL) were calculated. Focal segmental glomerulosclerosis patients receiving a zero mismatch LRD kidney transplant had the lowest ADGL rate, losing 10.5 grafts per 1000 patients per year. Not significantly different but higher (14.3) was the ADGL rate for LD, zero mismatch GN recipients. The ADGL rate was significantly higher in FSGS recipients who received a LD, mismatched transplant (36.5). Focal segmental glomerulosclerosis patients who received a CAD, zero mismatched graft (44.1), or CAD, mismatched graft (63.2), had significantly higher ADGL rates. Zero mismatch LRD kidney transplants are not a risk factor for graft loss in FSGS patients but are associated with significantly better death-censored graft survival as compared to CAD 6-antigen match or mismatched donations.