Minimal change nephropathy and focal segmental glomerulosclerosis

The terms minimal change nephropathy and focal segmental glomerulosclerosis describe histopathological entities diagnosed by renal biopsy, typically in patients presenting with heavy proteinuria and its consequences including nephrotic syndrome. Numerous alterations in the immune response have been reported, but there is uncertainty about whether these play a causal role. In both conditions, there is evidence of injury to glomerular epithelial cells (podocytes), a cell type with limited potential for repair or replacement. The mechanisms of injury are poorly understood but may include immunologically mediated processes such as the effects of soluble mediators produced by lymphocytes. Empirical immunosuppressive therapy with corticosteroids, alkylating agents, and/or calcineurin antagonists is often effective, but the potential for toxicity of these drugs is enormous, and more specific forms of treatment are needed. The focus in recent years has been on the podocyte, and in particular the potential importance of mutations/polymorphisms in podocyte-specific genes as predisposing factors, mechanisms of podocyte injury including study of the role of podocytes as active participants in disease pathogenesis, indices of podocyte injury as markers of disease activity or possible diagnostic tools, and strategies for podocyte repair including the recognition that existing therapies may have effects (beneficial or adverse) on podocytes. Future improvements in the understanding of these diseases and in our ability to successfully treat them can be confidently expected as a result of rapid advances in the study of podocyte biology in health and disease.     

Glomerular podocyte vacuolation in focal segmental glomerulosclerosis

An electron microscopic study of the nonsclerotic glomeruli or nonsclerosed segments of affected glomeruli was made in 34 children with nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) and in 34 children with minimal-change nephrotic syndrome. Particular attention was paid to alterations of glomerular epithelium. The most striking glomerular change in FSGS was vacuolation of the epithelial cell. Glomerular epithelial vacuolation was found in 21 of the 34 patients with FSGS. Eleven of these 21 patients with vacuoles developed chronic renal failure, while only one of the 13 patients without vacuoles developed renal failure. In minimal-change nephrotic syndrome only five of the 34 patients showed mild epithelial vacuolation. These observations are consistent with glomerular epithelial vacuolation contributing to the development and progression of the glomerular lesion in FSGS.     

Recurrent focal segmental glomerulosclerosis after renal transplantation

In a young adult male with chronic renal failure from focal segmental glomerulosclerosis, massive proteinuria appeared within two weeks after transplantation. Although allograft biopsy at eight weeks was normal, a second biopsy eight months after transplant showed focal segmental glomerulosclerosis again. Sixteen months after transplantation maintenance hemodialysis had to be restarted.     

Clinicopathological characteristics of obesity-associated focal segmental glomerulosclerosis

Obesity-related glomerulopathy (ORG) is a secondary form of focal segmental glomerulosclerosis (FSGS) occurring in obese patients with a body-mass index higher than 30?kg/m(2). It is typically manifested by nephrotic-range proteinuria without full nephrotic syndrome, and progressive renal insufficiency. Characteristic morphologic features include the consistent presence of glomerulomegaly, predominance of perihilar variant of FSGS, and the relatively mild fusion of visceral epithelial cell foot processes. The concept of podocyte depletion as a driver of the glomerular scarring in obesity-associated FSGS is well documented. The underlying mechanisms are likely to be related in part to the oxidative stress and the impairment of the integrity of the slit diaphragm and cell adhesion resulting mainly from angiotensin II and transforming growth factor-β. These proapoptotic cytokines are upregulated in obesity in response to insulin resistance, compensatory hyperinsulinemia and glomerular hyperfiltration-hypertension mediated mechanical stress. This review is designed to discuss the clinicopathologic features of obesity-associated FSGS, with a focus on the podocyte injury, which is involved in the onset and progression of the glomerulosclerotic process. Ultrastructural glomerular lesions are documented.     

Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.     

Cyclosporin a treatment in children with minimal change nephrotic syndrome and focal segmental glomerulosclerosis

Summary In a pilot study 23 children with nephrotic syndrome were treated with cyclosporin A (Cs) for 6–45 months. 8 children suffered from steroid dependent minimal change nephrotic syndrome (MCNS) and had experienced at least one course with cytotoxic drugs, but had relapsed thereafter. 2 children had diabetes mellitus type I with nephrotic syndrome and 13 children had steroid resistant focal segmental glomerulosclerosis (FSGS). Cs was started with 100 mg/m2/day in two doses and increased stepwise to obtain a Cs whole blood trough level of 200–400 ng/ml. In steroid dependent MCNS treatment with Cs reduced relapse rate significantly, and prednisone therapy could be stopped completely. After discontinuation of Cs, relapses reoccurred as frequently as before. Renal function remained unimpaired despite repeated Cs treatment courses up to 38 months. In cases of nephrotic syndrome with diabetes type I Cs treatment led to complete remission without changing the insulin requirement. However, after discontinuation of Cs relapses reoccurred. In steroid resistant FSGS 6 children benefited from Cs treatment: 4 went into complete remission, 2 into partial remission. The 2 children with complete remission relapsed but remained Cs responsive. The remaining 7 children with FSGS did not respond to Cs but continued the course of their disease, with two patients rapidly progressing to terminal renal failure. Side-effects of Cs treatment were mild. It is concluded that Cs is an effective agent in steroid dependent MCNS and can be used as an alternative drug in specific cases like steroid toxicity or diabetes mellitus. In steroid resistant FSGS a trial with Cs seems to be warranted since some cases do respond favorably. To avoid nephrotoxicity treatment with Cs should always be monitored closely by determination of blood levels and renal function.Abbreviations MCNS minimal change nephrotic syndrome - FSGS focal segmental glomerulosclerosis - Cs Cyclosporin A     

Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.     

A spectrum of morphologic lesions of focal segmental glomerulosclerosis by Columbia criteria in human immunodeficiency virus infection

The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five types of glomerular lesions, designated collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar (PH), and not otherwise specified (NOS) variant lesions. FSGS COLL and non-collapsing variants of FSGS are described in human immunodeficiency virus (HIV)-associated kidney disease. This study examined the range and relationships of Columbia-type segmental sclerosing lesions in biopsies from patients with HIV infection. We identified 47 renal biopsies from 46 patients with HIV infection obtained over an 8-year period. Twenty-seven biopsies from 26 patients had FSGS. Sixteen biopsies had FSGS COLL (59.3%), 3 had CELL (11.1%), 5 had NOS (18.5%), 2 had PH (7.4%), and 1 had GTL (3.7%) by the Columbia classification. Biopsies had more than one type of Columbia FSGS lesion in 63% and one type in 37%. Single types of FSGS lesions were identified in eight of eight biopsies with ≤10 glomeruli. Combinations of lesions were observed in 17 of 19 (89.5%) with >10 glomeruli, and the coincidence of COLL, CELL, and NOS lesions was not random. NOS, COLL, and CELL morphologic lesions of FSGS frequently coexist in kidney biopsies from HIV+ patients. Combined patterns of FSGS suggest that lesions identified by Columbia criteria may be part of a spectrum of responses to injury in the setting of HIV infection.     

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

不同病理类型局灶节段性肾小球硬化症的临床病理分析

目的探讨不同病理类型局灶节段性肾小球硬化症（FSGS）的临床病理特征及其与临床表现的关系。方法对北京大学第一医院2000年1月—2005年12月收集的102例特发性FSGS进行回顾性病理阅片及分型,并对其活动性及慢性化病理改变进行定量评估,分析不同病理类型FSGS的病理变化及其临床表现的特征。结果102例FSGS中,非特殊型占55．9％,门部型占6．9％,细胞型占25．5％,顶端型占4．8％,塌陷型占6．9％。细胞型和顶端型FSGS的尿蛋白水平较非特殊型明显增高,塌陷型和顶端型FSGS的肾病综合征比例较其他三型明显升高（x^2=12．23,P＜0．05）,细胞型和塌陷型FSGS的病理活动性积分较其他3型明显增高（P＜0．05）;门部型FSGS的病程较其他4组患者明显增高,其病理慢性化积分较顶端型和非特殊型明显增高（P＜0．05）;顶端型FSGS的病理总积分最少,明显低于细胞型和塌陷型（P＜0．05）;其慢性化积分较非特殊型和门部型明显降低（P＜0．05）。结论非特殊型FSGS是特发性FSGS的主要病理类型;塌陷型和细胞型FSGS是病变处于活动性阶段的病理类型,门部型FSGS为病理改变呈慢性化的病理类型,顶端型FSGS是病理改变最轻的病理类型。     

A case of focal segmental glomerulosclerosis associated with aplastic anemia

The pathogenic mechanism of focal segmental glomerulosclerosis (FSGS) and aplastic anemia are associated with immunologic events which lead to glomerular cell injury or hematopoietic cell destruction. We present an extremely rare case of FSGS with aplastic anemia in a 30-yr-old woman. The laboratory examination showed hemoglobin 7.2 g/dL, white blood count of 4,200/ microL, platelet count 70,900/microL. Proteinuria (2+, 3.6 g/day) and microscopic hematuria were detected in urinalysis. The diagnosis of FSGS and aplastic anemia were confirmed by renal and bone marrow biopsy. She was treated with immunosuppressive therapy of prednisone 60 mg/day orally for 8 weeks and cyclosporine A 15 mg/kg/day orally. She responded with gradually improving her clinical manifestation and increasing peripheral blood cell counts. Prednisone was maintained at the adequate doses with tapering after 8 weeks and cyclosporine was given to achieve trough serum levels of 100-200 ng/mL. At review ten month after diagnosis and initial therapy, the patient was feeling well and her blood cell counts increased to near normal (Hb 9.5 g/dL, Hct 32%, WBC 8,300/microL, platelet 123,000/microL) and renal function maintains stable with normal range proteinuria (0.25 g/day).     

Glomerular cells and macrophages in the progression of experimental focal and segmental glomerulosclerosis.

To determine the characteristics of glomerular cell involvement in experimental focal and segmental glomerulosclerosis (FGS) in rats induced by repeated injections of aminonucleoside of puromycin (PAN) and protamine sulfate (PS), glomeruli were isolated and grown in tissue culture. When compared with saline controls the FGS rats had decreased rates of glomerular attachment and significantly reduced outgrowths of type 1 (epithelial) and type II (mesangial) cells. However, the FGS rats had greater numbers of type III cells (macrophages) present in the outgrowths than controls. The production of interleukin-1 (IL-1) in the glomerular culture supernatant, measured by thymocyte stimulating activity, was determined at various stages throughout the evolution of FGS and in saline controls. The FGS glomeruli early in the disease course (day 10) had higher levels of IL-1 activity than glomerular outgrowths from control rats but significantly lower levels of IL-1 were produced late in the disease (day 80). Glomerular macrophages were present throughout the evolution of the disease but in greater numbers early (day 10). In this experimental model of FGS, IL-1 production, has been demonstrated early in the disease process, could originate from macrophages and/or mesangial cells, and could be involved in the progressive glomerulosclerosis.     

Thrombotic thrombocytopenic purpura and focal segmental glomerulosclerosis associated with the use of ecstasy

Ecstasy is a drug, which causes serious side effects and sometimes it can be lethal. These effects are due to idiosyncratic reactions as a result of various stimulations in adrenergic receptors. Here we present a case of a 36-year-old male patient who was diagnosed with thrombotic thrombocytopenic purpura associated with the use of ecstasy. Plasmapheresis along with methylprednisolone treatment restores patient condition to normal.