Sera from patients with collapsing focal segmental glomerulosclerosis increase albumin permeability of isolated glomeruli

The collapsing variant of focal segment glomerulosclerosis (FSGS) is characterized by heavy proteinuria and rapid progression to renal failure. Its cause is not known. We have characterized a substance in the circulation of patients with classic FSGS that increases in vitro permeability of glomeruli to albumin (P(alb)) and causes proteinuria when injected into rats. Inclusion of normal serum prevents the increase in P(alb) caused by this FSGS factor. We investigated the effect of sera from patients with collapsing FSGS on P(alb), as well as the effect of inclusion of normal serum. Isolated glomeruli were incubated with serum from each of 11 patients with collapsing FSGS (1:50 dilution) or with patient serum and an equal volume of pooled normal serum. P(alb) was determined on the basis of changes in glomerular volume in response to an oncotic gradient. Sera from 10 of the 11 patients with collapsing FSGS increased P(alb) of isolated glomeruli to a value of 0.5 or greater. In each of the 5 cases tested, inclusion of normal serum abolished the increase in P(alb). Sera of patients with collapsing FSGS increased glomerular P(alb). Our finding that the increase in P(alb) is abolished by normal serum suggests that the substance and its mechanism of action are similar or identical to the FSGS factor we have isolated from the plasma of patients with recurrent FSGS. The presence of a circulating factor in collapsing FSGS has implications for prognosis and treatment in primary and recurrent collapsing FSGS.     

Inverted formin 2‐related Charcot‐Marie‐Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons

Mutations in the gene encoding inverted formin FH2 and WH2 domain‐containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot‐Marie‐Tooth neuropathy combined with FSGS (FSGS–CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate‐type CMT and revealed occasional abnormal in‐ and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS‐CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT‐FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT‐FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2‐binding partner CDC42 in myelination.     

Exclusion of homozygous PLCE1 (NPHS3) mutations in 69 families with idiopathic and hereditary FSGS

Focal and segmental glomerulosclerosis (FSGS) is the most common glomerular cause of end-stage kidney disease (ESKD). Although the etiology of FSGS has not been fully elucidated, recent results from the positional cloning of genes mutated in nephrotic syndromes are now beginning to provide insight into the pathogenesis of these diseases. Mutations in PLCE1/NPHS3 have recently been reported as a cause of nephrotic syndrome characterized by diffuse mesangial sclerosis (DMS) histology. One single family with a missense mutation had late onset of the disease that was characterized by FSGS. To further define the role of PLCE1 mutations in the etiology of FSGS, we performed mutational analysis in 69 families with FSGS. A total of 69 families with 231 affected individuals were examined. The median age of disease onset was 26 years (range 1–66 years). Onset of ESKD was at a median age of 35.5 years. Seven variants leading to non-synonymous changes were found, of which only two are new variants (exon 4 c.1682 G>A R561Q, exon 31 c.6518A>G K2173R). No known disease-causing mutations were identified in the families screened. PLCE1/NPHS3 mutations are not a cause of FSGS in this cohort. The absence of mutations in PLCE1/NPHS3 in this study indicates that there are additional genetic causes of FSGS and that hereditary FSGS is a heterogeneous disease. Kindreds appropriate for genome-wide screening are currently being subjected to analysis with the aim of identifying other genetic causes of FSGS.     

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．     

中西医结合治疗原发性膜性肾病合并FSGS一例

文中列举了中西医结合治疗原发性膜性肾病合并FSGS一例,说明激素联合CTX?配合中医辨证治疗IMN合并FSGS,临床效果满意。     

Association of macrophage migration inhibitory factor −173C allele polymorphism with steroid resistance in children with nephrotic syndrome

The potential effects of macrophage migration inhibitory factor (MIF) on the natural immune response are due to the inhibition of immune cell activation, which is regulated by glucocorticoids. In this study, we investigated MIF –173G/C genotype and C allele frequency in 214 patients with idiopathic nephrotic syndrome (INS) and 103 healthy volunteers. We found significant increases in GC genotype (OR=3, p=0.0009) and C allele frequency (OR=2.5, p=0.0007) in INS. Upon classifying patients as steroid responsive (n=137) or resistant (n=77), a 20-fold over-expression of the CC-genotype was found in the steroid-resistant group (OR=20, p=0.0002). Moreover, a significant increase in C allele frequency in patients with focal segmental glomerulosclerosis (FSGS) has also been noted when compared with other histopathological groups (OR=3.2, p=0.0017). Furthermore, significant increases in the CC genotype (15.6% vs 3.3%) and C allele (75% vs 32%) frequencies have been found in patients with permanent renal function failure (p=0.013 and p=0.0002, respectively). Patients with the CC genotype were found to be at considerably increased risk of permanent renal failure (OR=5.43, p=0.013) and end-stage renal disease (OR=5.53, p=0.020). Additionally, there was a correlation between age of detection of proteinuria and CC genotype. We found an earlier age of onset of proteinuria in patients with the CC genotype (1.9±1.7 years) than in patients who were GC-heterozygous (3.7±3.1 years) and GG-homozygous (3.6±2.9 years, p=0.88). In summary, our results indicate that the MIF –173 C allele confers an increased risk of susceptibility to INS and plays a crucial role in glucocorticoid responsiveness.