Pathogenesis and therapy of focal segmental glomerulosclerosis: an update

Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Pediatric Nephrology (Impact Factor: 2.88). 11/2010; 26(7):1001-15. DOI: 10.1007/s00467-010-1692-x
Source: PubMed

ABSTRACT Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.

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    ABSTRACT: Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a progressive and proteinuric kidney disease that starts with podocyte injury. Podocytes cover the external side of the glomerular capillary by a complex web of primary and secondary ramifications. Similar to dendritic spines of neuronal cells, podocyte processes rely on a dynamic actin-based cytoskeletal architecture to maintain shape and function. Brain Derived Neurotrophic Factor (BDNF) is a pleiotropic neurotrophin that binds to the tropomyosin-related kinase B receptor (TrkB) and has crucial roles in neuron maturation, survival, and activity. In neuronal cultures, exogenously added BDNF increases number and size of dendritic spines. In animal models, BDNF administration is beneficial in both central and peripheral nervous system disorders. Here we show that BDNF has a TrkB-dependent trophic activity on podocyte cell processes; by affecting microRNA-134 and microRNA-132 signaling, BDNF upregulates Limk1 translation and phosphorylation, and increases cofilin phosphorylation which results in actin polymerization. Importantly, BDNF effectively repairs podocyte damage “in vitro”, and contrasts proteinuria and glomerular lesions in “in vivo” models of FSGS, opening a potential new perspective to the treatment of podocyte disorders.
    The Journal of Pathology 11/2014; 235(5). DOI:10.1002/path.4484 · 7.33 Impact Factor
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    ABSTRACT: FSGS is a molecularly heterogeneous disease, and can be classified into primary or secondary disease. Primary FSGS can be due to immune or genetic causes. To date, more than 20 genes have been implicated in FSGS. The discovery of so many FSGS genes, together with the advent of next-generation sequencing, has led to a paradigm shift in the genetic diagnosis and management of this disease. However, genetic screening in FSGS may not be so straightforward because of the difficulty in selection and prioritization of genes. It is challenging to appreciate the prevalence of mutations in the different genes based on the current literature due to heterogeneity of the studies and rarity of the disease. Clinicians need to understand the different methods of genetic screening available. These should be weighed against practical issues such as clinical urgency, financial costs, availability of expertise, and test accessibility. Clinicians should also consider the likelihood of a genetic etiology and the clinical impact of a genetic diagnosis to decide, with the patient and family, on the extent or “aggressiveness” of the genetic screening. The main impact of a genetic diagnosis in FSGS is on the use of immunosuppressive medications as well as on peri-transplant management involving the selection of live-related donors and risk of post-transplant recurrence.
    12/2014; 3(1). DOI:10.1007/s40124-014-0064-6
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    ABSTRACT: Background: Treatment of steroid-resistant nephrotic syndrome with a focal segmental glomerulosclerosis (FSGS) histological diagnosis can be challenging, particularly in the presence of ciclosporin resistance. The importance of mutations in genes encoding the structural proteins of podocytes has been recently recognized and may influence medical decision-making. The c.349G>A variant of the NPHS1 gene has been associated with a poorer prognosis in IgA nephropathy and nephrotic syndrome. Case Diagnosis/Treatment: To study the potential association of the NPHS1: c.349G>A sequence variant with renal disease, we analyzed five children in whom this variant had been identified and who all presented with nephrotic syndrome and the histological diagnosis of FSGS. Although this sequence variant was present in all cases, one patient had steroid-responsive nephrotic syndrome without relapse following standard initial therapy, three responded to a variety of treatments, and one patient was unresponsive. Conclusion: The NPHS1: c.349G>A sequence variant may either be independent of, or a modifying agent in, the progression of the disease, and does not preclude these and similar patients from appropriate treatment and entry into clinical trials. Larger trials are needed to evaluate the therapeutic response and long-term outcome of FSGS patients with different NPHS gene mutations.
    04/2014; 2(1):9-13. DOI:10.12970/2310-984X.2014.02.01.2

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