Familial focal segmental glomerulosclerosis

There is increasing recognition of the importance of genetic factors in the development of focal segmental glomerulosclerosis and related proteinuric disorders. Recently, four genes have been identified which, when defective, cause focal segmental glomerulosclerosis or nephrosis. All of these genes appear to be important in the maintenance of glomerular podocyte function. However, not all cases of familial nephrosis or proteinuria are explained by defects in these genes.     

Idiopathic focal segmental glomerulosclerosis

Idiopathic focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that essentially represents a form of chronic, progressive renal fibrosis for which there is no discernible cause. Often presenting with or eventually manifesting the nephrotic syndrome, this disease is increasing in incidence in both children and adults. Therapy continues to be a challenge, although some patients clearly respond to corticosteroids or cyclosporine with a decrease in, or remission of, proteinuria. A favorable response is associated with a decreased likelihood of progression to kidney failure. Given our clinical experience and recent advances in understanding the genetics of FSGS, a stochastic model of disease pathogenesis can be proposed.     

Pathophysiology of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS. KR is a Pediatric Nephrology Trainee supported by grant no. NIH T32 DK007110 30. FJK is supported in part by NIH DK63549-04.     

Genetics of focal segmental glomerulosclerosis

The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease.     

Treatment of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) has been increasing in incidence over the past 2 decades and may currently be the most common form of primary nephrotic syndrome in the United States. Nephrotic patients with FSGS who do not achieve a remission in proteinuria usually advance to end-stage renal disease within 5 to 10 years. Although initially felt to be a steroid-resistant disease, especially in adults, studies show significant responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or steroid-dependent FSGS, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Other agents used include pulse methylprednisolone, azathioprine, tacrolimus, mycophenolate mofetil, and combination therapy. For recurrent FSGS after renal transplantation, plasmapheresis is often used but appears not to be as efficacious in adults as in the pediatric population.     

Treatment of focal segmental glomerulosclerosis

The prognosis of untreated patients with focal segmental glomerulosclerosis is poor, as the disease progress to end-stage renal disease in approximately 50--70% of nephrotic patients. Although focal segmental glomerulosclerosis was initially considered to be a steroid-resistant disease, several studies have shown a better responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or -dependent focal segmental glomerulosclerosis, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Plasmapheresis or LDL-apheresis may represent a rescue treatment in patients who do not respond to other therapies. The role of other agents used in focal segmental glomerulosclerosis, including azathioprine, mycophenolate mofetil, tacrolimus, pefloxacin or vitamin E is still poorly defined.     

Familial collapsing focal segmental glomerulosclerosis

The majority of patients with non-HIV-related collapsing focal segmental glomerular sclerosis (FSGS) have idiopathic disease. Only a few genetic forms associated with rare syndromes have been described in families. Here we report two families with multiple members who have collapsing FSGS with no clear associated secondary etiology. Genetic analysis revealed a defect in the TRPC6 gene in one family, but excluded all known common inherited podocyte defects in the other family. The course and response to treatment differed dramatically among members of the same family.     

Microarray analysis of focal segmental glomerulosclerosis

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of chronic renal failure in children. Recent studies have begun to define the molecular pathogenesis of this heterogeneous condition. Here we use oligonucleotide microarrays to obtain a global gene expression profile of kidney biopsy specimens from patients with FSGS in order to better understand the pathogenesis of this disease. METHODS: We extracted RNA from renal biopsy samples of 10 patients with the diagnosis of FSGS and from 5 control kidney samples, and produced labeled cRNA for hybridization to Affymetrix human U133A microarrays. RESULTS: We identified a gene expression fingerprint for FSGS that contained 429 of 22,283 possible genes, each with a p < 0.01, using RMA normalization, Welch t test, and at least a 1.8-fold change in 5 of the 10 patients examined. We also found gene expression differences in samples from subsets of patients who had either nephrotic syndrome or renal insufficiency. This screen identified many genes and genetic pathways that have already been implicated in the pathogenesis of FSGS. In addition, we found changes in gene expression in genetic pathways that have not been studied in FSGS. CONCLUSIONS: Oligonucleotide DNA microarray analysis of renal biopsy specimens identified a gene expression fingerprint in samples from a heterogeneous population of patients with FSGS. The genes and genetic pathways identified in this study can be compared to results of similar studies of other diseases to examine specificity and used to study the pathogenesis of FSGS.     

Permeability factors in focal segmental glomerulosclerosis

The pathologic diagnosis of focal segmental glomerulosclerosis (FSGS) is associated with a syndrome of steroid-resistant nephrotic syndrome and progressive renal insufficiency. The incidence of FSGS has increased in recent years. Known causes of FSGS include genetic abnormalities, viral infections, decreased nephron number, and hyperperfusion/hyperfiltration. The etiology is unknown in the majority of cases. FSGS recurs after initial renal transplantation in as many as 30% to 50% of patients. Recent studies have verified the hypothesis that plasma of patients with FSGS contains a factor or factors that increase permeability of glomerular capillaries and cause proteinuria after injection into rats. Patients who experience posttransplant recurrence of FSGS and those with rapidly progressive disease exhibit this activity. Permeability activity has been verified in functional assays and defined by measurement of albumin permeability (P(alb)) or glomerular volume variation (GVV). Permeability activity is decreased by plasmapheresis or immunoadsorption and can be recovered from discarded plasma or eluate from adsorption materials. Studies from our laboratory indicate that permeability activity is carried by small, highly glycosylated, hydrophobic protein(s)/peptide(s). Normal plasma contains substances capable of blocking or inactivating the FSGS permeability factor. Pharmacologic agents including cyclosporine, indomethacin, and derivatives of Trypterigium wilfordii also block permeability activity in vitro. The observation that permeability activity can be blocked by diverse agents raises hope that specific therapy may be designed for FSGS. Future investigations will permit identification of the active FSGS permeability factor, of mechanisms that initiate and perpetuate proteinuria, and of interventions to prevent renal failure in native kidneys and recurrence of disease in renal allografts.     

Rituximab for refractory focal segmental glomerulosclerosis

We present the cases of two children with steroid-resistant nephrotic syndrome (SRNS) who were treated with rituximab (anti-CD20 monoclonal antibody). Both were resistant to conventional therapy, and renal biopsy showed focal segmental glomerulosclerosis (FSGS). Combination therapy with methylprednisolone pulse therapy and plasmapheresis was the only way to decrease proteinuria. However, the patients suffered severe reactions to steroid treatment. We therefore treated them with rituximab in a single dose of 375 mg/m², which resulted in the rapid clearing of circulating CD19-positive B cells. One month after rituximab treatment, both achieved partial remission; one patient has maintained complete remission for 8 months, and the other relapsed 8 months after the first rituximab treatment with the recovery of peripheral B-cell counts and received a second rituximab treatment. She achieved complete remission 5 months after the second course and has maintained the remission for 2 months. We conclude that rituximab may be an effective treatment for refractory SRNS with FSGS.     

Hepatitis B complicated focal segmental glomerulosclerosis

After the initial report of membranous glomerulopathy due to hepatitis B virus infection by Combes et al, other glomerular diseases - but rarely focal segmental glomerulosclerosis (FSGS) association with HBV infection - have been reported. Herein we present an 8-year-old boy with chronic HBV infection complicated FSGS. The patient was initially regarded as idiopathic FSGS and started on an immunosuppressive schedule. The elevation of liver transaminases in the course of the therapy revealed the immunotolerated perinatal HBV infection. It was considered that immunosuppressive agents have induced viral replication. The treatment was changed to lamivudine alone. The nephrotic syndrome has already been improved with the seroconversion of anti-HBeAg and reduced liver functional tests by the tenth month of the treatment. This case is peculiar for the seldom association of FSGS with chronic HBV infection and treatment modality particularly for the countries where this viral infection is endemic.     

肥胖相关性局灶节段性肾小球硬化症临床与病理表现

目的探讨局灶节段性肾小球硬化症(FSGS)患者中,肥胖病例是否存在特殊临床及病理表现.方法收集我院1998年10月～2002年7月经肾穿刺活检确诊为FSGS的病例,其中体重指数(BMI)≥28 kg/m2者共13例(肥胖组),将其与同期BMI＜24 kg/m2(非肥胖组)的13例患者进行临床、实验室及病理表现比较.结果(1)肥胖组中,2例伴发2型糖尿病,2例糖耐量异常,12例原发性高甘油三酯血症,2例原发性高尿酸血症,而非肥胖组中,除12例为继发性高甘油三酯血症外,无其它代谢疾病;(2)肥胖组蛋白尿(3.91±2.83)g/24h,血浆白蛋白(39.25±2.80)g/L;非肥胖组蛋白尿(4.43±1.81)g/24h,血浆白蛋白(24.23±10.11)g/L,两组血浆白蛋白水平差异有显著性意义(P＜0.05);肾病综合征发生率肥胖组(0/13)显著低于非肥胖组(9/13)(P＜0.01);水肿发生率肥胖组(4/13)显著低于非肥胖组(11/13)(P＜0.01);(3)肥胖组肾小球直径为(229.89±26.18)μm,与非肥胖组(177.18±29.94)μm间差异有显著性意义;(4)肥胖组虽较非肥胖组病程长,但其肾功能指标、肾小球硬化及肾间质纤维化程度均优于非肥胖组.结论肥胖组患者常伴发糖、脂肪或嘌呤代谢紊乱;虽有大量蛋白尿,但血浆白蛋白水平多正常;病理检查可见肾小球肥大;肾功能损害进展较慢.