Treatment of membranous nephropathy: Perspectives on current and future therapies.

Primary membranous nephropathy remains one of the most frequent causes of nephrotic syndrome in adults. It is an autoimmune disorder in which auto-antibodies target antigens at the podocytes cell membrane-basement membrane interface. Our understanding of membranous nephropathy has expanded dramatically as of late. After the initial discovery of the phospholipase A2 receptor auto-antibody in 2009, eight more antigens have been discovered. These discoveries have led to refinement in our understanding of the pathogenesis, diagnosis, and natural history of primary membranous nephropathy. Now, many experts advocate for redefining primary membranous nephropathy based on antigen, potentially shedding the primary and secondary nomenclature. Recently, therapies for primary membranous have also expanded. Immunosuppressive therapies like cyclophosphamide and rituximab, which primarily target B-cells, remain the cornerstone of therapy. However, there is still significant room for improvement, as many as 30-40% do not respond to this therapy according to recent trials. Additionally, drugs targeting complement, and other novel therapies are also under investigation. In this review we will discuss the available therapies for primary membranous nephropathy in light of recent clinic trials like GEMRITUX, MENTOR, RI-CYCLO, and STARMEN, as well as management strategies. While the last 10 years have seen a boom in our mechanistic understanding of this ever-diversifying disease, we are likely to see a similar boom in the therapeutic options in the years to come.

The Evolving Role of Novel Biomarkers in Glomerular Disease: A Review.

Recent advances in glomerular biology have expanded our understanding of glomerular diseases, leading to more precise therapeutic options. Since the discovery of the autoantigen phospholipase A2 receptor in primary membranous nephropathy 10 years ago, the serologic evaluation of glomerular diseases has become more detailed and nuanced for nephrologists. In addition to phospholipase A2 receptor antibodies, circulating autoantibodies now include thrombospondin type 1 domain-containing 7A and most recently, neural epidermal growth factor-like 1 protein for membranous nephropathy. Additionally, discoveries in C3 glomerulopathy and fibrillary glomerulonephritis are poised to improve the diagnostic approach to these disorders by using novel biomarkers to complement traditional histologic patterns on kidney biopsy. Although kidney biopsies are considered the gold standard in profiling glomerular diseases, validated novel glomerular biomarkers contribute substantially to the diagnostic and therapeutic approaches through their ability to improve sensitivity, permit dynamic longitudinal monitoring of disease activity, and capture genetic heterogeneity. We describe the value of specific biomarkers in selected glomerular diseases, with the major focus on their clinical applicability.

Podocyte histone deacetylase activity regulates murine and human glomerular diseases.

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Telavancin-associated acute kidney injury
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Telavancin is a lipoglycopeptide semi-synthetic derivative of vancomycin used for select infections caused by Gram-positive bacteria including Staphylococcus aureus. Human clinical trials suggest that telavancin is potentially nephrotoxic, however there is no histopathologic description of acute kidney injury (AKI) in humans. An animal model has recently characterized the histologic changes associated with telavancin-induced AKI as proximal tubular injury with numerous phagolysosomes. We present a case of a 47-year-old man with methicillin-resistant Staphylococcus aureus bacteremia treated with telavancin, who developed AKI after 5 weeks of intravenous therapy. Acute tubular injury with lysosomal proliferation and acute interstitial nephritis were observed on kidney biopsy. To our knowledge, this is the first reported case of AKI due to telavancin that has documented kidney histopathology.
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Urine Sediment Examination in the Diagnosis and Management of Kidney Disease: Core Curriculum 2019.

Automated urine technology and centralized laboratory testing are becoming the standard for providing urinalysis data to clinicians, including nephrologists. This trend has had the unintended consequence of making examination of urine sediment by nephrologists a relatively rare event. In addition, the nephrology community appears to have lost interest in and forgotten the utility of provider-performed urine microscopy. However, it is critical to remember that urine sediment examination remains a time-honored test that provides a wealth of information about the patient's underlying kidney disease. This test performs very favorably as a urinary "biomarker" for a number of acute kidney diseases. When used properly, urine sediment findings alert health care providers to the presence of kidney disease, while also providing diagnostic information that often identifies the compartment of kidney injury. Urine sediment findings may also guide therapy and assist in prognostication. In this review of the role of urine sediment examination in the diagnosis and management of kidney disease, we seek to help experienced nephrologists maintain their competency in performing this test and encourage ongoing training of nephrology fellows and others less experienced in such analyses.