Glomerular Microangiopathy with Cellular Crescent-like Formation and Endotheliopathy Due to Ramucirumab Treatment for Metastatic Sigmoid Colon Cancer

We encountered a 77-year-old Japanese man who presented with nephrotic-range proteinuria 20 days after receiving ramucirumab treatment for metastatic sigmoid colon cancer. A kidney biopsy showed two characteristic histological findings. The first finding was podocyte injury with cellular crescent-like formation, although focal segmental glomerulosclerosis (FSGS) (collapsing variant) according to the Columbia classification may have been a more appropriate name for this injury, as hypertrophy and hyperplasia of epithelial cells, presumably resulting from podocyte injury, were seen between Bowman''s capsule and the glomerular basement membrane (GBM); these changes appeared to be due to the collapse of the GBM rather than to GBM destruction with fibrinoid necrosis. The second finding was endotheliopathy characterized by prominent mesangial interposition via enlargement of the mesangial matrix with mesangiolysis. Proteinuria and renal dysfunction subsided after discontinuation of ramucirumab. Bevacizumab has been reported to induce glomerular microangiopathy with endothelial damage and swelling six months after treatment, but in this case, ramucirumab may have induced focal segmental glomerulosclerosis (FSGS) collapsing variant and glomerular microangiopathy with endotheliopathy via mesangial damage within 1 month. We believe that the damage to the glomerular podocyte and endothelial cells via mesangial damage secondary to ramucirumab in our patient was a different type of glomerular microangiopathy than the endothelial cell damage with enlargement of the subendothelial space caused by bevacizumab.     

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。     

雷公藤甲素对局灶节段性肾小球硬化足细胞损伤的调控机制

目的:通过观察雷公藤甲素(TP)对局灶节段性肾小球硬化(FSGS)大鼠及PAN致小鼠足细胞损伤模型中uPAR和TRPC6的表达影响,探讨TP对足细胞的保护作用。方法:将48只大鼠随机分为6组,Control组、Model组、TP-LD组、TP-MD组、TP-HD组和CSA组。除Control组外,其余各组均通过单侧肾切除联合尾静脉重复注射阿霉素方法建立FSGS大鼠模型,药物组给予不同浓度TP或CSA进行治疗,干预8周后处死。检测大鼠24h尿蛋白、血肌酐、尿素氮。HE染色观察肾组织病理变化,电镜观察肾小球足细胞病变。Western Blot检测肾组织中uPAR和TRPC6蛋白表达。培养小鼠肾足细胞MPC5,分为正常组(Control组)、PAN组(Model组)、PAN+TP组(TP组)、PAN+CSA组(CSA组)。CCK-8法检测TP对于PAN诱导的足细胞活力的影响,Western Blot检测足细胞uPAR、TRPC6蛋白水平的表达。结果:Model组大鼠尿蛋白、血肌酐及尿素氮水平较Control组显著升高(P<0.01),肾脏病理检查可见小球局灶节段性硬化,小管扩张及足突融合。Western Blot发现,与Control组比较,Model组Podocin表达下降,TRPC6及uPAR表达显著升高(P<0.01)。经TP干预后,大鼠尿蛋白、血肌酐、尿素氮及肾脏病理显著改善,肾组织Podocin表达升高,TRPC6、uPAR表达下降。随着TP浓度升高,足细胞保护作用逐步增强,高浓度TP的作用效果与CSA基本相似。细胞实验进一步证实MPC5经PAN作用48h后,Podocin表达显著下降,TRPC6及uPAR表达明显上升,TP治疗可有效逆转上述改变。结论:TP可通过下调TRPC6及uPAR起到保护足细胞,改善FSGS的作用。     

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.     

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.     

Complete remission of nephrotic syndrome in an infant with focal segmental glomerulosclerosis: is it renin–angiotensin blockade?

Nephrotic syndrome presenting in the first year of life is often challenging, with substantial risk of progression to end-stage renal disease (ESRD). Focal segmental glomerulosclerosis (FSGS) comprises up to 20% of biopsy-proven glomerular disease in children and adults. We report on a 9-month-old infant who presented with nephrotic syndrome, hypertension and progressive deterioration of renal function due to FSGS. As immunosuppressive agents are often unsuccessful in treating this condition, we adopted renoprotection as the mainstay treatment for this patient, through rigorous control of blood pressure and proteinuria with a multi-drug regimen including renin-angiotensin axis blockade. Initially, there was partial improvement, with a gradual decline in proteinuria and a concomitant rise in the glomerular filtration rate, before the disease eventually passed into complete clinical and laboratory remission. We speculate that infants with steroid-resistant nephrotic syndrome due to FSGS may benefit from tight control of hypertension, mainly though early blockade of the renin-angiotensin axis. We believe that its renoprotecive mechanism counteracts the deleterious effects of both hypertension and proteinuria, thereby not only preventing progressive renal disease, but even paving the way for a remission, as in our patient. To the best of our knowledge, this is the first report of an infant with nephrotic syndrome (NS) due to FSGS that passed into complete remission while the patient was on renoprotective measures including the use of angiotensin-converting enzyme inhibitors (ACEis).     

Primary focal segmental glomerular sclerosis in children: clinical course and prognosis

To review the clinical course and identify prognostic factors, we retrospectively analyzed 92 children with steroid-resistant primary focal segmental glomerulosclerosis (FSGS). The mean age of onset was 80.4+/-42.4 months. The mean follow-up duration was 98.2+/-63.3 months. Eighty-five patients presented with nephrotic syndrome and seven presented with asymptomatic proteinuria. Thirty-three patients were initial responders to steroid treatment (late non-responders) and 59 were initial nonresponders. At last follow-up, 36 patients (39.1%) were in complete remission, and 29 (31.5%) progressed to chronic renal failure (CRF). Renal survival rates at 5, 10, and 15 years were 84, 64, and 53%, respectively. By morphological classification, there were tip variants (6.1%), collapsing variants (10.6%), cellular variants (1.5%), perihilar variants (9.1%), and NOS (not otherwise specified, 72.7%). Among the variants, there were no significant differences in age of onset, degree of proteinuria, response to treatment, or progression to CRF. Poor prognostic factors for CRF included: asymptomatic proteinuria at presentation, initial renal insufficiency, higher segmental sclerosis (%), severe tubulointerstitial change, initial nonresponse, and absence of remission. In the multivariate analysis, an increase in the initial serum creatinine and resistance to treatment were independent risk factors for CRF. A more prolonged use of corticosteroid therapy and early introduction of cyclosporin A (CsA) may improve the prognosis for primary FSGS in patients with initial steroid nonresponsiveness.