- CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease. [Journal Article]
- AJAm J Kidney Dis 2018 Nov 09
- CONCLUSIONS: Current follow-up can only detect large differences in ESKD and death outcomes.Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.
- The Role of Glucocorticoid Receptors in Podocytes and Nephrotic Syndrome. [Journal Article]
- NRNucl Receptor Res 2018; 5
- Glucocorticoid receptor (GC), a founding member of the nuclear hormone receptor superfamily, is a glucocorticoid-activated transcription factor that regulates gene expression and controls the develop...
Glucocorticoid receptor (GC), a founding member of the nuclear hormone receptor superfamily, is a glucocorticoid-activated transcription factor that regulates gene expression and controls the development and homeostasis of human podocytes. Synthetic glucocorticoids are the standard treatment regimens for proteinuria (protein in the urine) and nephrotic syndrome (NS) caused by kidney diseases. These include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) or subsequent complications due to diabetes mellitus or HIV infection. However, unwanted side effects and steroid-resistance remain major issues for their long-term use. Furthermore, the mechanism by which glucocorticoids elicit their renoprotective activity in podocyte and glomeruli is poorly understood. Podocytes are highly differentiated epithelial cells that contribute to the integrity of kidney glomerular filtration barrier. Injury or loss of podocytes leads to proteinuria and nephrotic syndrome. Recent studies in multiple experimental models have begun to explore the mechanism of GC action in podocytes. This review will discuss progress in our understanding of the role of glucocorticoid receptor and glucocorticoids in podocyte physiology and their renoprotective activity in nephrotic syndrome.
- Apolipoprotein A-Ib as a biomarker of FSGS recurrence after kidney transplantation: Diagnostic performance and assessment of its prognostic value - a multi-centre cohort study. [Journal Article]
- TITranspl Int 2018 Nov 08
- Recurrence of idiopathic FSGS is a serious complication after kidney transplantation. FSGS relapse is suspected by a sudden increase in proteinuria but there is not an accurate non-invasive diagnosti...
Recurrence of idiopathic FSGS is a serious complication after kidney transplantation. FSGS relapse is suspected by a sudden increase in proteinuria but there is not an accurate non-invasive diagnostic tool to confirm this entity or to detect patients at risk. We aimed to validate the diagnostic performance of ApoA-Ib to detect FSGS relapses by measuring urinary ApoA-Ib in a retrospective cohort of 61 kidney transplanted patients (37 FSGS and 24 non-FSGS). In addition, to assess the ApoA-Ib predictive ability, ApoA-Ib was measured periodically in a prospective cohort of 13 idiopathic FSGS patients who were followed during one year after transplantation. ApoA-Ib had a sensitivity of 93.3% and a specificity of 90.9% to diagnose FSGS relapses, with a high negative predictive value (95.2%), confirming our previous results. In the prospective cohort, ApoA-Ib predated the recurrence in 4 out of 5 episodes observed. In the non-relapsing group (n=9), ApoA-Ib was negative in 37 out of 38 samples. ApoA-Ib has the potential to be a good diagnostic biomarker of FSGS relapses, providing a confident criterion to exclude false positives even in the presence of high proteinuria. It has also the potential to detect patients at risk of relapse, even before transplantation. This article is protected by copyright. All rights reserved.
- Nephrotic syndrome associated with Kimura's disease: a case report and literature review. [Journal Article]
- BNBMC Nephrol 2018 Nov 08; 19(1):316
- CONCLUSIONS: MCD combined with acute renal tubular injury is rare in patients with KD presenting with renal involvement. Corticosteroids may be a beneficial treatment for renal injury in patients with KD.
- Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population. [Journal Article]
- FPFront Pediatr 2018; 6:307
- Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discover...
Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (χ2p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.
- Successful recovery of associated interstitial nephritis and focal segmental glomerulosclerosis in patients with HCV and HIV treated with sofosbuvir and daclatasvir and revision of literature. [Journal Article]
- CNClin Nephrol Case Stud 2018; 6:31-35
- In this report, we describe the coexistence of two rare and debated complications of hepatitis C virus (HCV) infection: interstitial nephritis, with associated focal glomerulosclerosis, and autoimmun...
In this report, we describe the coexistence of two rare and debated complications of hepatitis C virus (HCV) infection: interstitial nephritis, with associated focal glomerulosclerosis, and autoimmune hepatitis, in a 55-year-old HIV/HCV-coinfected woman. The patient was treated for the immune-mediated manifestations with mycophenolate mofetil, which she continued for 9 years, as symptoms relapsed at every attempt to discontinue immunosuppression. The patient finally cleared HCV infection thanks to new direct-acting agents and could discontinue immunosuppressive therapy maintaining stable conditions and laboratory parameters after 24-weeks follow-up.
- A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer. [Journal Article]
- CRCase Rep Oncol Med 2018; 2018:6927639
- We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively comm...
We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively common side effect of VEGF-targeted treatments and can occasionally result in treatment discontinuation. Here, we describe a patient who developed secondary FSGS necessitating discontinuation of treatment at first but who was subsequently rechallenged with anti-VEGF-targeted treatment without recurrence of proteinuria. Lenvatinib was a novel experimental agent at the time the treatment took place; however, its recent licensing for the treatment of thyroid malignancies in the UK makes reporting of these adverse effects all the more important now.
- Generation of two isogenic iPS cell lines (IRFMNi002-A and IRFMNi002-B) from a patient affected by Focal Segmental Glomerulosclerosis carrying a heterozygous c.565G>A mutation in PAX2 gene. [Journal Article]
- SCStem Cell Res 2018 Oct 29; 33:175-179
- Focal Segmental Glomerulosclerosis (FSGS) is the typical renal histologic lesion in familial steroid-resistant nephrotic syndrome, for which there is currently no treatment. Dysfunction of the glomer...
Focal Segmental Glomerulosclerosis (FSGS) is the typical renal histologic lesion in familial steroid-resistant nephrotic syndrome, for which there is currently no treatment. Dysfunction of the glomerular podocyte, a specialized cell that forms the glomerular filtration barrier, is central in the pathogenesis of FSGS. Here, we reported the generation of two isogenic iPS cell lines from a patient affected by FSGS, carrying the c.565G > A mutation in the PAX2 gene. The iPS cell lines we generated expressed pluripotency markers at the mRNA and protein levels and differentiated into all three germ layers. These iPSCs will be instrumental in understanding FSGS pathogenesis.
- The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis. [Journal Article]
- JBJ Biol Chem 2018 Nov 02
- Focal segmental glomerulosclerosis (FSGS) is a common kidney disease that results in nephrotic syndrome. FSGS arises from dysfunction and apoptosis of podocytes in the glomerulus of the kidney, leadi...
Focal segmental glomerulosclerosis (FSGS) is a common kidney disease that results in nephrotic syndrome. FSGS arises from dysfunction and apoptosis of podocytes in the glomerulus of the kidney, leading to podocytopathy. The molecular mechanisms underlying podocyte apoptosis remain incompletely understood. Using an array of gene expression profiling, PCR and in situ hybridization assay, we found here that the levels of the long noncoding RNA LOC105374325 were elevated in the renal podocytes of individuals with FSGS. We also observed that the microRNAs miR-34c and miR-196a/b down-regulated the expression of the apoptosis regulators BCL2-associated X, apoptosis regulator (Bax) and BCL2 antagonist/killer 1 (Bak) in podocytes. Competitive binding between LOC105374325 and miR-34c or miR-196a/b increased Bax and Bak levels and caused podocyte apoptosis. Of note, the mitogen-activated protein kinase P38 and the transcription factor CCAAT enhancer-binding protein β (C/EBPβ) up-regulated LOC105374325 expression. P38 inhibition or C/EBPβ silencing decreased LOC105374325 levels and inhibited apoptosis in Adriamycin-treated podocytes. LOC105374325 overexpression decreased miR-34c and miR-196a/b levels, increased Bax and Bak levels, and induced proteinuria and focal segmental lesions in mice. In conclusion, the activation of the P38/C/EBPβ pathway stimulates the expression of LOC105374325, which, in turn, increases Bax and Bak levels and causes apoptosis by competitively binding to miR-34c and miR-196a/b in the podocytes of individuals with FSGS.
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- Clinical Management of Glomerular Diseases. [Review]
- NCNurs Clin North Am 2018; 53(4):551-567
- Progressive glomerular damage can occur as a result of various etiologic factors including infections, medications, diseases, and autoimmune disorders. This article discusses the clinical management ...
Progressive glomerular damage can occur as a result of various etiologic factors including infections, medications, diseases, and autoimmune disorders. This article discusses the clinical management of the leading conditions associated with glomerular disease, including glomerulosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy. Glomerular damage and disease progression may lead to end stage renal disease. Clinical management is individualized, as based on causative factors and clinical manifestations, with the overall goal of limiting glomerular damage. Collaborative and comprehensive care is imperative to improving patient outcomes.