肝素防治局灶节段性肾小球硬化的实验研究

目的　观察肝素钙注射液防治局灶节段性肾小球硬化 (FSGS)的可能性。方法　 18只 Wistar大鼠随机分为正常对照组 (A组 )、肝素治疗组 (B组 )和模型组 (C组 )。采用小剂量分次阿霉素间羟胺高脂饲料法建立大鼠 FSGS模型 ,B组于实验第 2 9d予肝素钙注射液治疗。各组均测定 2 4 h尿蛋白、血生化指标及肾脏组织血流量 ,并在光镜和电镜下检查肾脏形态、肾小球硬化指数 (SI)及细胞外基质 (ECM)。结果　治疗后 2周 (实验 6周 )时肝素治疗组尿蛋白排泄量开始降低 ,实验 12周时肝素治疗组胆固醇升高的幅度低于模型组。肝素治疗组肾组织血流量明显增加。光镜检查显示 ,肝素治疗组 SI及 ECM/肾小球面积 (GA)均明显减低 ;电镜检查显示 ,肝素治疗组毛细血管腔通畅 ,基底膜改变及足突融合均较模型组明显减轻。结论　肝素对FSGS有一定的防治作用。     

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.     

Therapeutic plasma exchange in recurrent focal segmental glomerulosclerosis following transplantation

Focal segmental glomerulosclerosis (FSGS) recurs in 30% of renal allograft transplants with graft loss in half of the cases. A humoral factor may be implicated. We report on the use of therapeutic plasma exchange (TPE) in 11 patients with recurrent FSGS post transplantation. Medical records from 1989-2000 were reviewed for 11 adults transplanted for biopsy proven FSGS. Ten patients developed proteinuria (x: 6.1 g; range: 3-40 g/24 h) within 2 months of transplantation. In 1 patient, proteinuria (4 g) occurred 2 years post transplantation. Biopsy in six patients revealed early recurrent FSGS, while in five, suspected recurrence was based on clinical findings. Each patient received 5-11 TPEs (x: 6) with the COBE Spectra, daily or on alternate days with 2.5-3.5 L 5% albumin as the replacement fluid. In four, FFP was included because of coagulopathy. All received immunosuppression (IS) during and after TPE. A persistent drop in 24 h urine protein (U.P.) was observed in 10/11 patients. Seven had >70% drop in 24 h U.P. following the course of TPE, while three had a reduction of 45-50%. No change occurred in 1 patient. Follow-up (9 months-5 years) of seven patients has shown a persistent U.P. of <1 g with successful allograft survival. In these patients, TPE appeared effective in early recurrent FSGS. The decrease in U.P. may result from combined TPE and IS. Although the disease is designated in category III by the ASFA, TPE should be considered early when FSGS recurrence is established.     

Increased glomerular and extracellular malondialdehyde levels in patients and rats with focal segmental glomerulosclerosis

BACKGROUND: Evidence suggests an increase in oxidative stress in patients with chronic kidney disease, as glomerulosclerosis is the prerequisite for chronic kidney disease; whether the oxidative stress already exists early on is not known. MATERIALS AND METHODS: In this study we measured the plasma and urinary levels of malondialdehyde (MDA), the end product of lipid peroxidation, and assessed the immunoreactivity of MDA and superoxide dismutase (SOD) in glomeruli of patients and rats with primary focal segmental glomerulosclerosis (FSGS), and compared our findings with those of minimal change disease (MCD) and normal controls (NC). RESULTS: Our results showed that plasma MDA level was significantly increased in patients with FSGS compared with both patients with MCD and normal controls. The urinary MDA level was also significantly increased and was significantly correlated with plasma MDA level in patients with FSGS. The immunostaining for glomerular MDA and SOD was significantly higher in the patients with FSGS than in either the patients with MCD or NC, and was also significantly higher in rats with puromycin aminonucleoside (PAN)-induced FSGS than in rats with MCD. Glomerular MDA level was significantly correlated with the degree of glomerulosclerosis in the patients with FSGS. CONCLUSIONS: Our data suggest that oxidative stress occurs early on before the onset of renal failure, and may play an important role in the pathogenesis of glomerulosclerosis.     

End‐stage renal disease in a child with focal segmental glomerulosclerosis associated with a homozygous NUP93 variant

This report highlights that the genetic causes of FSGS, including NUP93 gene variant, such as the one described in this report, progress to end‐stage renal disease rapidly and that the risk of recurrence post‐renal transplantation is less likely.     

Long-term plasmapheresis therapy in the management of focal segmental glomerulosclerosis recurrence after kidney transplantation

The recurrence of primary focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) appears in 30 % of the recipients. Sometimes it can cause the loss of the allograft. Although many treatments for this condition have been reported, 20 %–40 % of the affected patients are refractory or presents frequents relapses. In this paper we describe the evolution of three recipients treated with long-term plasmapheresis therapy after a recurrence of FSGS with a bad or incomplete response to other treatments. Although our findings require confirmation, long-term plasmapheresis could be a therapeutic option for this condition.     

Reduced podocyte expression of alpha3beta1 integrins and podocyte depletion in patients with primary focal segmental glomerulosclerosis and chronic PAN-treated rats

Integrins attach cells to extracellular matrix (ECM) and mediate signals from ECM to cells or from cells to ECM. They regulate cell functions, including adhesion, migration, cell cycle regulation, and differentiation. Podocytes may detach from the glomerular basement membrane (GBM) and be excreted in the urine, and proteinuria is found in patients with primary focal segmental glomerulosclerosis (FSGS); both may be associated with loss of alpha3beta1integrins. In this study, we have examined the podocyte number in patients with primary FSGS and normal controls, and the alpha3- and beta1-integrin subunits expression of podocytes in patients with primary FSGS and chronic puromycin aminonucleoside (PAN)-treated rats by the morphometric, immunoperoxidase histochemical, and immunoelectron microscopic examination. We also measured their expression serially in rats that received repeated PAN injection. The results showed that the podocyte number was significantly decreased in patients with primary FSGS than in normal control (P < 0.05). The immunostaining score showed that both alpha3- and beta1-integrin subunits on podocytes in patients with primary FSGS were significantly lower than in normal controls (both P < 0.01). The number of immuno-gold particles of alpha3- and beta1-integrins at the effaced foot process area of patients with primary FSGS were also significantly decreased than that of normal controls (both P < 0.05). The immunostaining score of both alpha3- and beta1-integrin subunits was negatively correlated with the degree of glomerular sclerosing score and the amount of daily protein loss, and they were positively correlated with the number of podocytes. Chronic 12-week PAN-treated rats showed similar findings with decreased immunostaining expression and immuno-gold particles of alpha3-integrin on podocytes than in normal control (both P < 0.05). The chronic PAN-treated rats also showed a trend toward gradually decreased immunostaining expression of alpha3-integrin subunit on podocyte during the progress from normal to FSGS state. These studies indicate that podocyte expression of alpha3- and beta1-integrin subunits is significantly reduced in humans with primary FSGS and chronic PAN-treated rats, before the morphological changes of FSGS are observed. The decreased podocyte expression of alpha3beta1 integrins is closely related with podocyte depletion, glomerular sclerosis, and daily protein loss in patients with primary FSGS.     

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.     

A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes.     

Primary focal segmental glomerulosclerosis: clinical and morphological prognostic factors

AIM: To retrospectively analyze clinical course and results of immunodepressive therapy of patients with primary focal-segmental glomerulosclerosis (FSGS), to reveal prognostic factors of the disease progression and patients' sensitivity to immunosuppressive therapy. MATERIAL AND METHODS: Morphological diagnosis was specified, morphological indices of activity and sclerosis were estimated, renal survival was analysed, mono- and multivariate analysis of prognostic factors was made by the evidence obtained in the study of 135 biopsy specimens from CRF patients meeting the criteria of FSGS. RESULTS: At the moment of the disease onset only age of the patients was related to FSGS: 5- and 10-year survival was 100% if the disease started under 16 years of age, if older--the survival was 80 and 65%, respectively. Nephrotic syndrome, hematuria, high creatinine, racemose alterations in the glomeruli worsened the disease prognosis. When cytostatics and corticosteroids were used in combination they produced better results and were associated with better prognosis than each of them in monotherapy. Patients with marked hematuria and low proteinuria were less sensitive to therapy than those with weak hematuria and high proteinemia. Patients with FSGS having high IA and SI required more aggressive therapy for response. CONCLUSION: Renal biopsy with quantitation of IA and IS increases the prognosis accuracy and is important for choice of the treatment policy in patients with primary FSGS.     

Plasma endothelin-1 levels in liver cirrhosis

The role of circulating endothelin- , a potent vasoconstricting peptide, in liver cirrhosis is still controversial. It has been postulated that endothelin-1 may play a role in the circulatory derangement occurring in cirrhotic subjects, and increased plasma endothelin-1 levels have been reported in these patients. In this study we looked for a relationship between the severity of the liver disease according to Child's classification and plasma endothelin-1 concentrations in a group of cirrhotic patients compared with a healthy control group. Twenty-two cirrhotic patients and 10 healthy controls, matched for sex and age, were selected for study after informed consent. The etiology of cirrhosis was posthepatitis B in 8 of 22 cases, posthepatitis C in 13 of 22 cases, and alcoholism in 1 patient. According to Child's classification, 6 patients were in class A, 6 in class B, and 10 in class C. Plasma endothelin-1 was measured by a commercial RIA kit (Amersham UK). Mean +/- SD plasma endothelin-1 levels were 8.8 +/- 0.9 pg/ml in controls and 9.2 +/- 1.1 pg/ml in all cirrhotic patients (P > 0.05). In each sub-group of cirrhotics, plasma endothelin- was 8.6 +/- 1.2 pg/ml in Child A, 8.9 +/- 1.9 pg/ml in Child B, and 10.6 +/- 1.5 pg/ml in Child C groups, respectively. There were no statistical differences between control subjects and Child A and B cirrhotic patients (P > 0.05). A significant increase in endothelinl was observed only in the Child C group versus either group A or B (P = 0.004). Our results show that alterations of circulating endothelin-1 do not occur in all cirrhotic patients; higher plasma levels than controls are only detectable in patients with more-severe hepatic failure. We do not know whether increased endothelin-1 levels are a consequence of hemodynamic disorders occurring in the advanced phase of liver cirrhosis or play a pathogenic role.     

A novel compound heterozygous variant in SMARCAL1 leading to mild Schimke immune-osseous dysplasia identified using whole-exome sequencing

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive inherited disorder that is caused by the SMARCAL1 mutation. The phenotype can vary from mild to severe on the basis of the patient’s age at onset. Herein, we report the case of a 14-year-old Chinese boy who presented with short stature, focal segmental glomerulosclerosis (FSGS), and facial dysmorphism. Genetic analysis revealed two compound heterozygous missense mutations, including a well-known mutation (c.1933C>T, p.R645C) and a novel mutation (c.2479G>A, p.V827M) in the SMARCAL1 gene, which were inherited from his parents. In silico analyses showed that the c.2479G>A (p.V827M) variant affects a highly conserved residue within the ATPase catalytic domain. Finally, we established the diagnosis of mild SIOD and treated the patient with diuretics and angiotensin receptor blockers. This report expands the mutational spectrum of SMARCAL1 and reinforces the importance of a detailed clinical evaluation, molecular detection, and appropriate genetic counseling.     

筛查某家族性局灶节段硬化性肾小球肾炎家庭的NPHS2基因

目的 为某个有两个儿童患者死于局灶节段硬化性肾小球肾炎的家庭查找致病原因.方法 取孕18周后的羊水进行染色体检查,同时提取夫妇静脉血DNA、死亡男童肾组织DNA及胎儿羊水DNA,进行NPHS2基因检测.结果 胎儿染色体未见异常;孕妇NPHS2基因检测发现c.954C＞T变异,此改变位于第8外显子,不引起氨基酸的改变,为...     

Opa1 Overexpression Protects from Early-Onset Mpv17−/−-Related Mouse Kidney Disease

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Nephrotic syndrome in minimal change disease (kidney), focal segmental glomerulosclerosis,and focal mesangioproliferative glomerulonephritis

AIM: To specify clinical and laboratory characteristics of minimal change disease (MCD), focal mesangioproliferative glomerulonephritis (MPGN), focal-segmental glomerulosclerosis (FSGS). MATERIAL AND METHODS: A retrospective analysis of 45 case histories of children (renal biopsy for nephrotic syndrome) has shown that morphologically 13 of them had MCD, 15--FSGS and 17--focal MPGN. Clinical, laboratory, immunofluorescent and electron microscopy findings typical for each of the morphological types were studied. RESULTS: The data obtained suggest that MCD, FSGS and focal MPGN may represent independent forms of glomerulonephritis. CONCLUSION: If a differential diagnosis by renal biopsy is difficult, information from the disease history and clinico-laboratory evidence should be used.     

Removal of focal segmental glomerulosclerosis (FSGS) factor suPAR using CytoSorb

Treatment of primary focal segmental glomerulosclerosis (FSGS) and its recurrence after kidney transplantation associated with rapid deterioration of kidney function remains to be challenging despite advances in immunosuppressive therapy. The presence of circulating factors has been postulated to be a pivotal player in the pathogenesis of FSGS, although suPAR and CLCF‐1 have been identified as the most promising causative factors. The potential therapeutic effect of suPAR elimination in an FSGS patient using CytoSorb, a hemoadsorption device that gained attention in the cytokine elimination in septic patients, was studied. Efficiency of total plasma exchange to remove suPAR was determined. CytoSorb hemoadsorption caused a 27.33% reduction of the suPAR level in a single treatment, whereas total plasma exchange showed a suPAR level reduction of 25.12% (n = 3; 95% confidence interval, 0.2777‐0.8090; P < 0.01), which may indicate therapeutic potential in the treatment of primary FSGS and its recurrence in a kidney transplant.