This is a report of a patient with minimal change disease (MCD) onset after bevacizumab administration. A 72-year-old man with inoperable Grade 3 astrocytoma was treated with a combination of temozolomide and the vascular endothelial growth factor monoclonal antibody bevacizumab. After two biweekly treatments, he developed nephrotic syndrome. Despite cessation of bevacizumab, his renal function deteriorated and a renal biopsy disclosed MCD. Thereafter, he was started on high-dose oral prednisone and renal function immediately improved. Within weeks, the nephrotic syndrome resolved. Although rare, biologic agents can cause various glomerulopathies that can have important therapeutic implications. MCD should be considered in patients who develop nephrotic syndrome while exposed to antiangiogenic agents.
BackgroundThe genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (Os) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the Os mutation. The Os mutation leads to FSGS in multiple strains including the ROP-Os/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-Os/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis.MethodsTo identify such novel genes, which regulate susceptibility or resistance to renal disease progression, we generated and compared the renal transcriptomes using serial analysis of gene expression (SAGE) from the sclerosis-prone ROP-Os/+ and sclerosis resistant C57-Os/+ mouse kidneys. We confirmed the validity of the differential gene expression using multiple approaches. We also used an Ingenuity Pathway Analysis engine to assemble differentially regulated molecular networks. Cell culture techniques were employed to confirm functional relevance of selected genes.ResultsA comparative analysis of the kidney transcriptomes revealed multiple genes, with expression levels that were statistically different. These novel, candidate, renal disease susceptibility/resistance genes included neuropilin2 (Nrp2), glutathione-S-transferase theta (Gstt1) and itchy (Itch). Of 34 genes with the most robust statistical difference in expression levels between ROP-Os/+ and C57-Os/+ mice, 13 and 3 transcripts localized to glomerular and tubulointerstitial compartments, respectively, from micro-dissected human FSGS biopsies. Network analysis of all significantly differentially expressed genes identified 13 connectivity networks. The most highly scored network highlighted the roles for oxidative stress and mitochondrial dysfunction pathways. Functional analyses of these networks provided evidence for activation of transforming growth factor beta (TGFβ) signaling in ROP-Os/+ kidneys despite similar expression of the TGFβ ligand between the tested strains.ConclusionsThese data demonstrate the complex dysregulation of normal cellular functions in this animal model of FSGS and suggest that therapies directed at multiple levels will be needed to effectively treat human kidney diseases.
Chronic renal disease initiation and progression remain incompletely understood. Genomewide expression monitoring should clarify the mechanisms which cause progressive renal disease by determining how clusters of genes coordinately change their activity. Serial analysis of gene expression (SAGE) is a technique of expression profiling which permits simultaneous and quantitative analysis of 9- to 13-bp sequence tags that correspond to unique mRNAs. Key principles of the technique are use of PCR in a manner to minimize distortion and serial concatenation of tags which facilitates sequencing and permits identification of many expressed genes in a single cDNA molecule. Tags are extracted from many concatenated sequences, counted using software, and identified by comparison with existing gene databases. In aggregate, gene expression profiles generated from a tag library comprise a transcriptome which represents a comprehensive and quantitative profile of genes expressed at the time of analysis. These global snapshots of gene expression patterns can better define basic cell biology and provide insights into disease pathogenesis by simultaneously determining the net consequences of gene-gene and gene-environment interactions on expression of thousands of genes. Rather than applying a priori assumptions (i.e., hypothesis testing), transcriptome analysis is hypothesis generating and requires no prior knowledge of gene expression. SAGE kidney transcriptomes, from normal animals and animals with progressive kidney disease, are being produced and can be analyzed for novel pathogenetic mechanisms. The use of SAGE and other genomic and proteomic tools should result in a better understanding of kidney disease pathogenesis and in identification of new therapeutic targets.
Continuous renal replacement therapy (CRRT) is an essential tool in the management of renal failure in patients who are critically ill. Though its utilization has increased globally, it is a resource-intensive, costlier modality of dialysis. [1][2][3][4] Furthermore, its usage is highly variable owing to the heterogeneity of patients and physicians, as well as the paucity of evidence to guide practice. 5 These characteristics make it a prime target for high-value care through standardization of practice. At our institution, we assessed utilization patterns of CRRT and established evidence-based guidelines to standardize process flow and promote meaningful use.Methods | A multidisciplinary task force was organized in October 2015 to assess CRRT utilization patterns. Interventions were implemented throughout fiscal year (FY) 2016, including the creation of evidence-based guidelines that: (1) clarified each physician's role in the initiation, maintenance, and cessation of CRRT; (2) defined indications to start therapy with a focus on patient goals of care; (3) described situations where CRRT would be medically inappropriate; (4) mandated daily cross-disciplinary communication between medical teams and key stakeholders; and (5) provided guidance on discontinuing CRRT. Additional measures to minimize excess laboratory tests and promote awareness of CRRT were also implemented. Comparisons between preintervention (FY 2014(FY -2015 and postintervention (FY 2016(FY -2017) cohorts were made with the independent samples t test for continuous variables, and Pearson
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